MXPA00011213A - Use of amyloid inhibitors for modulating neuronal cell death. - Google Patents

Abstract

The invention provides methods of inhibiting Abeta-induced neuronal cell death. The invention further provides methods of providing neuroprotection to a subject and methods of treating a disease state characterized by Abeta-induced neuronal cell death in a subject. Methods of inhibiting p75 receptor mediated neuronal cell death, as well as methods of treating a disease state in a subject characterized by p75 receptor mediated neuronal cell death are provided.

Description

USE OF AMYLOID INHIBITORS FOR THE MODULATION OF THE DEATH OF NEURONAL CELLS FIELD OF THE INVENTION This invention relates to methods for modulating the death of 5 neuronal cells. BACKGROUND OF THE INVENTION Amyloid-β (Aß) is a neurotoxic peptide involved in the pathogenesis of Alzheimer's disease. In fact, the extracellular deposit of Aβ peptide in specific JWLO regions of the brain is one of the hallmarks of Alzheimer's disease. The Aβ peptide is derived from a normal proteolytic dissociation of the precursor protein, the amyloid-β precursor protein (βAPP). Once deposited in the brain, the Aß peptide forms senile plaques that have 15 found in a large number of the brains of patients with Alzheimer's disease. It has also been shown that Aβ peptide infiltrates the cerebrovascular walls and causes angiopathy. A progressive loss of neuronal cells accompanies the deposition of amyloid fibrils Aß in plaques 20 senile. Several groups have shown that the Aβ peptide is highly toxic to neurons. Amyloid plaques are directly associated with reactive gliosis, dystrophic neurites and apoptotic cells, suggesting that plaques induce neurodegenerative changes. In vitro, it has 25 shown that Aß is necrotic in rat PC-12 cells while inducing apoptosis in primary hippocampal culture from fetal rat and in the SH-SY5Y cell line of a pre-differentiated human neurotype (Li et al. (1996) Brain ßearch 738: 196-204). Neurodegeneration associated with AD has been related to the presence of fibrillar Aβ. Several reports have shown that Aß fibrils can induce neurodegeneration. It has been hypothesized that this activity was due to the acquisition of the ß sheet structure of Aß. It has also been shown that non-fibrillar Aβ is cytotoxic to neurons. The Fair et al. ((1997) J. Clin Invest. 100 (2): 310-320) have recently shown that when neuronal cells are exposed in vitro to soluble Aβ they can become apoptotic. Once internalized, the Aβ peptide stabilizes and induces DNA fragmentation, which is a characteristic of apoptosis. A major event in the formation of β-sheet fibrils is the binding of the Aß peptide with the sulphated proteoglycans present on the surface of the cell. It has been shown that the base membrane glycosaminoglycans (GAGs) interact with all types of amyloidotic proteins. It has been suggested that the interaction of GAGs with an Aβ peptide induces conformational changes by favoring aggregation and the formation of insoluble fibrils. It has also been shown that the nerve growth factor (NGF) enhances the neurotoxicity of Aβ in differentiated hippocampal neurons in culture (Yan ner B.A. et al. (1990) Proc. Nati. Acad. Sci. 87: 9020-23). It has been suggested that ß-amyloid deposits can induce NGF receptor induction in neuronal cell types, which typically do not respond to NGF. The mechanisms and specific molecules involved in the death of neuronal cells, such as the death of neuronal cells induced by Aβ peptide, remain uncertain. As a result, to date, no effective treatment has been developed for conditions associated with neuronal cell death, for example, neurodegenerative disorders. Accordingly, methods to inhibit the death of neuronal cells are still required. SUMMARY OF THE INVENTION The present invention offers methods for inhibiting the death of neuronal cells such as, for example, the death of neuronal cells induced by Aβ and / or the death of neuronal cells mediated by the p75 receptor. The present invention is based, at least in part, on the discovery of compounds that interfere with the association of the Aβ peptide, for example, the association of the Aβ peptide with sulfate GAGs present on the cell surface, and prevent the triggering of the apoptosis or necrosis of neuronal cells.

Accordingly, this invention relates to a method for inhibiting neuronal cell death induced by Aβ. The method includes contacting a neuronal cell • with an Aβ interferent, in such a way that said death of neuronal cells is inhibited. The Aβ interfering can interfere with the ability of the Aβ peptide to form amyloid fibrils and / or with the ability of the Aβ peptide to bind with a cell surface molecule. The cell surface molecule can be, for example, a receptor ¿Neurotrophic, for example, the receptor p75 related to apoptosis, a protein presented by plasma protein, for example RAGE; or a glycosaminoglycan. The Aβ peptide can be found either in soluble form or in the form of fibril. In one embodiment, the Aβ interferer is selected from the group consisting of ethanesulfonic acid, 1,2-ethanedisulfonic acid, 1-propanesulfonic acid, 1,3-propanedisulfonic acid, 1,4-butanedisulfonic acid, 1,5 acid pentanedisulfonic, 2-aminoethanesulfonic acid, 4- 20 hydroxybutan-1-sulfonic acid and pharmaceutically salts thereof. In other preferred embodiments the Aβ interferer is selected from the group consisting of 1-butanesulfonic acid, 1-decansulfonic acid, 2-propanesulfonic acid, 3-pentanesulfonic acid, 4-heptanesulfonic acid and pharmaceutically acceptable salts of the same. In other preferred embodiments, the Aβ interferer is 1,7-dihydroxy-4-heptanesulfonic acid, 3-amino-1-propanesulfonic acid, or a pharmaceutically acceptable salt thereof. In another embodiment, Aβ is a peptide or mimetic peptide that interacts with specific regions of the Aβ peptide such as the regions responsible for cellular adhesion (10-16), GAG binding site region (13-16) or the region responsible for sheet formation ß (16-21). These peptides are d-stereoisomers of Aβ or complementary image of the Aβ peptide. Another aspect of the invention relates to a method for providing neuroprotection to a subject, comprising administering an Aβ interfering to the subject, for the purpose of providing neuroprotection. In one embodiment, the Aβ interferer interferes with the ability of the Aβ peptide to bind to a cell surface molecule, e.g., a neurotrophic receptor such as the p74 receptor associated with apoptosis; a protein represented by a plasma protein, for example, RAGE; or a glycosaminoglycan. The Aβ peptide can be found either in soluble form or in the form of fibril. In one embodiment, the Aβ interferer is selected from the group consisting of ethanesulfonic acid, 1,2-ethanedisulfonic acid, 1-propanesulfonic acid, 1,3-acid. propandisulfonic, 1,4-butanedisulfonic acid, 1,5-pentanedisulfonic acid, 2-aminoethanesulfonic acid, 4-hydroxybutan-1-sulfonic acid, and pharmaceutically acceptable salts thereof. In other preferred embodiments, the Aβ interferer is selected from the group consisting of 1-butanesulfonic acid, 1-decansulfonic acid, 2-propanesulfonic acid, 3-pentanesulfonic acid, 4-heptanesulfonic acid and pharmaceutically acceptable salts thereof. In other preferred embodiments, the Aβ interferer is 1,7-dihydro-4-heptanesulfonic acid, 3-amino-1-propanesulfonic acid, or a pharmaceutically acceptable salt thereof. In one embodiment, the Aβ interferer is administered in a pharmaceutically acceptable formulation. The pharmaceutically acceptable formulation can be a dispersion system, such as, for example, a lipid-based formulation, a liposome formulation, or a multivesicular liposome formulation. The pharmaceutically acceptable formulation may also comprise a polymer matrix, selected for example from synthetic polymers such as polyesters (PLA, PLGA), polyethylene glycol, poloxomers, polyanhydrides, and pluronics, or selected from naturally occurring polymers such as albumin, alginate, cellulose, collagen, fibrin, gelatin, and polysaccharides. In other preferred embodiments, the The pharmaceutically acceptable formulation provides sustained administration of the Aβ interfering to a subject. Another aspect of the present invention relates to a method for treating a disease characterized by the death of neuronal cells induced by Aβ in a subject. The method includes the administration of an Aβ interferer to the subject, such that the disease characterized by the death of neuronal cells induced by Aβ is treated. Another aspect of the invention relates to a method for inhibiting neuronal cell death mediated by the p75 receptor. The method includes contacting a neuronal cell with a therapeutic compound having the structure: Q - [- Y "X +] n where Y ~ is an anionic group at physiological pH, Q is a vehicle group, X + is a group cationic; and n is an integer selected such that the biodistribution of the therapeutic compound for a predicted target site is not prevented while maintaining the activity of the therapeutic compound, provided that the therapeutic compound is not chondroitin sulfate A, in such a manner The neuronal cell death is inhibited A further aspect of the invention relates to a method for providing neuroprotection to a subject The method includes the administration to the subject of a compound therapeutic that has the structure: Q [Y "X +] n where Y" is an anionic group at physiological pH; Q is a vehicle group; X + is a cationic group; and n is an integer selected in such a way that the biodistribution of the therapeutic compound to a predicted target site is not impeded while maintaining the activity of the therapeutic compound, provided that the therapeutic compound is not chondroitin sulfate A, such that provide neuroprotection. In another aspect, the invention is a method for treating a disease in a subject that is characterized by neuronal cell death mediated by p75 receptor. The method includes administering to the subject a therapeutic compound having the structure: Q [Y "X +] n where Y" is an anionic group at a physiological pH; it is a vehicle group; X + is a cationic group; and n is an integer selected in such a way that the biodistribution of the therapeutic compound to a predicted target site is not impeded while maintaining the activity of the therapeutic compound, provided that the therapeutic compound is not chondroitin sulfate A, such that the Disease status characterized by neuronal cell death mediated by p75 receptor is treated.

In another aspect, the invention is a method for inhibiting neuronal cell death mediated by p75 receptor. The method includes the contacting of a neuronal cell with a p75 receptor interferer, which has the structure: X - (CYV J? CW XR3 RX z wherein Z is XR2 or R4; R1 and R2 are each independently hydrogen, a substituted or unsubstituted aliphatic group, an aryl group, a heterocyclic group, or a cation forming salt: R3 is hydrogen, lower alkyl, aryl, or a salt formation cation: R5 is hydrogen, lower alkyl, aryl or amino, X is, independently for each case, 0 or S; Y1 and Y2 are each one independently hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, or aryloxy, and n is an integer from 0 to 12, such that death of neuronal cells is inhibited In a further aspect, the invention features a method to provide neuroprotection to a subject The method includes the administration to the subject of a p75 receptor interferer having the structure: X wherein Z is XR2 or R4; R1 and R2 are each, independently, hydrogen, a substituted or unsubstituted aliphatic group, an aryl group, a heterocyclic group, or a salt formation cation; R3 is hydrogen, lower alkyl, aryl, or a salt formation cation; R 4 is hydrogen, lower alkyl, aryl or amino; X is, independently in each case, O or S; Y1 and Y2 are each independently hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, or aryloxy; and n is an integer of 0 15 to 12, in such a way that neuroprotection is provided. In another aspect, the invention presents a method for the treatment of a disease in a subject, characterized by the death of neuronal cells mediated by the p75 receptor. The method includes administration to the subject of a 20 receiver interferer p75 that has the structure: 25 wherein Z is' XR2 or R4; R1 and R2 are each, independently, hydrogen, a substituted or unsubstituted aliphatic group, an aryl group, a heterocyclic group, or a salt formation cation; R3 is hydrogen, lower alkyl, aryl, or a salt formation cation; R 4 is hydrogen, lower alkyl, aryl or amino; X is, independently for each case, 0 or S; Y1 and Y2 are each independently hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, or aryloxy; and n is a number 10 is from 0 to 12, such that said disease characterized by neuronal cell death mediated by p75 receptor is treated. Other features and advantages of the invention will be apparent from the following detailed description, and to 15 from the claims. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a representation of a bar graph showing the toxicity of Aβ (1-40) administered in a ratio of 1: 1 with several interfering Aβ, in cells 20 PC-12. Figure 2 is a representation of a bar graph showing the toxicity of Aβ (1-40) administered in a 1: 2 ratio with several Aβ interferers in PC-12 cells. 25 Figure 3 is a representation of a bar graph which shows the percentage of surviving cells of differentiated PC-12 cells treated with Aβ (1-40) and several types of Aβ interferers in a 1: 2 and 1: 1 ratio. Figure 4 is a representation of a bar graph showing the results from an Aβ-mediated neurotoxicity assay (1-40) in differentiated PC-12 cells. Figure 5 is a graph illustrating the ability of Aβ to induce the death of neuronal cells using the human cell line of neuroblastoma SH-5454. Toxicity was measured using two different assays: the WST-1 assay and the uptake of 3H-thiperidine. Figure 6 illustrates the ability of a compound of the present invention, NC-2125, to significantly reduce the toxicity induced by Aβ when incubated in a molar ratio Aβ: nc-2125 of 1: 4, laminin, used in a molar ratio Aß: 1:10"laminin 3 in an internal positive control (neuroprotective) DETAILED DESCRIPTION OF THE INVENTION The present invention is based, at least in part, on the discovery that compounds that interfere with the Aβ peptide, by For example, the association of the Aβ peptide, in sites present on the surface of the cell or in sulfate GAGs, avoid the triggering of apoptosis or necrosis of neuronal cells.

This invention relates to a method for inhibiting neuronal cell death induced by Aβ. The method includes contacting a neuronal cell with an interfering Aβ, in such a way that the death of neuronal cells is inhibited. As used herein, the term "contact" includes both in vivo and in vitro methods of placing an Aβ interfering or a p75 receptor interfering close to a neuronal cell, such that the Aβ interfering or the p75 interfering receptor interferes. can modulate, for example, inhibit, the death, as for example, apoptosis, of the neuronal cell. For example, the neuronal cell may be in contact with an Aβ interfering in vivo by administering the Aβ interfering to a subject either parenterally, e.g., intravenously, intradermally, subcutaneously, orally (e.g. inhalation), transdermally (topically), transmucosally or rectally. A neuronal cell may also be contacted in vitro for example by the addition of an interfering Aβ or interfering p75 receptor in a tissue culture dish where neuronal cells are cultured. The invention further relates to a method for providing neuroprotection to a subject, comprising the administration of an Aβ interfering to the subject, such that provide neuroprotection. As used herein, the term "subject" is intended to encompass susceptible animals from states characterized by the death of neuronal cells, preferably mammals, especially humans. In a preferred embodiment, the subject is a primate. In a still more preferred mode, the primate is a human being. Others, examples of subjects include experimental animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows. The experimental animal may be an animal model for a disorder such as, for example, a transgenic mouse with an Alzheimer-type neuropathology. A subject can be a human suffering from a neurodegenerative disease, such as Alzheimer's disease, or Parkinson's disease. As used herein, the term "neuroprotection" includes protection of neuronal cells from a subject against cell death, for example, cell death induced by an Aβ peptide and / or mediated by a p75 receptor related to apoptosis. Neuroprotection includes, for example, the inhibition of processes such as destabilization of the cytoskeleton; the activation of hydrolytic enzymes such as phospholipase A2, calcium activated proteases, and calcium-activated endonucleases; the disorder of cell junctions that lead to diminished or absent communication cell-cell; and the activation 'of expression of genes involved in cell death, for example, immediate-early genes. Interfering Aβ and interfering receptor p75 In one embodiment, the method of the present invention includes contacting an in vitro neuronal cell or administering to a subject in vivo an effective amount of an interfering α-Aβ or a p75 receptor interferer, having at least one anionic group or covalently linked to a carrier molecule. As used herein, an "Aβ interferer" refers to a compound that can interfere with the ability of an Aβ peptide to either form Aβ fibrils or to interact with a cell surface molecule such as a proteoglycan 15 constituent of a base membrane, for example, a glycosaminoglycan, a cell surface receptor, for example, a neurotrophic receptor such as for example the p75 receptor related to apoptosis; or a protein presented by plasma protein, for example, 20 RAGE. An interfering Aβ can interfere with the ability of fibrillar or non-fibrillar Aβ to interact with a cell surface molecule, eg, the p75 receptor related to apoptosis or RAGE. As used herein, a "p75 receptor interferer" refers to a compound 25 which may interfere with the capacity of the p75 receiver related to apoptosis to mediate cell death in a neuronal cell. The p75 receptor interferent can block a ligand binding site at the p75 receptor, It can compete with the natural ligand for binding to the p75 receptor, or it can block the binding site of the p75 receptor on the natural ligand, thus preventing ligand-receptor interaction. It will be understood that the description presented below refers to particular compounds, and the formulas are applicable to both examples? .0 of .Aß interferers and receiver interferers p75. The Aβ interferent or the p75 receptor interferer can have the following structure: Q - [- Y'X +] n where Y ~ is an anionic group at physiological pH; Q is a 15 vehicle group; X + is a cationic group; and n is an integer. The number of anionic groups ("n") is selected such that the biodistribution of the Aβ interferent or p75 receptor interferer for a predicted target site is not prevented while maintaining the activity of the interferent 20 of Aß or interferer of receiver p75. For example, the number of anionic groups is not large enough to prevent the crossing of an anatomical barrier, such as a cell membrane, or penetration into a physiological barrier, such as the blood-brain barrier in situations 25 in which such properties are desired. In one modality, n is a number between 1 and 10. In another embodiment, n is an integer between 3 and 8. These compounds are described in U.S. Patent No. 5,643,562, the contents of which are incorporated herein by reference. An anionic group of an Aβ interfering agent of the invention is a negatively charged portion which, when fixed on a carrier group, can inhibit an Aβ peptide either from forming Aβ fibrils or from interacting with a cell surface molecule as per example a proteoglycan constituting a base membrane, for example, a glycosaminoglycan, a cell surface receptor, for example, a neurotrophic receptor such as a p75 receptor related to apoptosis, or a protein presented by plasma protein, for example RAGE, thus preventing the death of the neuronal cell. An anionic group of a p75 receptor interferer of the invention is a negatively charged portion which, when fixed on a carrier group, can inhibit the p75 receptor related to apoptosis from mediating the cell death of a neuronal cell. For the purposes of this invention, the anionic group is negatively charged at physiological pH. Preferably, the anionic Aβ interferer mimics the structure of a sulphated proteoglycan, that is, it is a sulphated compound or a functional equivalent thereof. "Equivalents functional groups of sulfates include compounds such as sulphamates as well as bioisosteres.Biosisers encompass both classical bioisostomeric equivalents and non-classical bioisostomeric equivalents.Standard and nonclassical bioisosteres of sulfate groups are known in the art (see, eg, Silverman , RB The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, CA, 1992, pages 19-23.) Accordingly, an Aβ interferer of the present invention can comprise at least one anionic group including sulfonates, sulfates, sulfamates, phosphonates, phosphates, carboxylates, and heterocyclic groups of the following formulas: 20 According to the vehicle group, they can be linked there more than an anionic group. When they bind more than an anionic group on a vehicle group, the multiple anionic groups can be the same structural group (for example, all sulfonates), or, alternatively, a combination of different groups 25 anionic agents can be used (for example, sulfonates, phosphonates, and sulphates, etc.). The ability of an Aβ interfering of the invention to inhibit an interaction between an Aβ peptide and a ^^ glycoprotein or proteoglycan constituting a base 5 membrane can be evaluated through an in vitro binding assay as for example through the assay described in Leveugle B. et al. (1998) J. of Neurochem. 70 (2): 736-744. In summary, a constituent of the base membrane, preferably a glycosaminoglycan (GAG) can be M radiolabelled, for example, in a specific activity of 10,000 cpm, and then incubated with Aβ-Sepharose peptide beads for example in a ratio of 5: 1 (volume / volume) in the presence or absence of the interfering Aß. Peptides of peptide Aß-Sepharose and radiolabelled GAG 15 can be incubated for approximately 30 minutes at room temperature and then the beads can be washed successively with a Tris buffer solution that V contains NaCl (0.55 M and 2 M). The binding of the base membrane constituent (eg, GAG) with the Aβ peptide can 20 then measured by collecting the fractions from the washings and subjecting them to scintillation counting. An Aβ interfering agent that inhibits an interaction between an Aβ peptide and a glycoprotein or a proteoglycan constituting a base membrane, for example GAG, 25 increases the amount of radioactivity detected in the washed. Preferably, an Aβ interferer of the present invention interacts with a binding site for a • base membrane glycoprotein or proteoglycan in an Aβ peptide and therefore inhibits the binding of the Aβ peptide to the base membrane constituent, eg GAG. Glycoproteins and base membrane proteoglycans include GAG, laminin, type IV collagen, fibronectin, and heparan sulfate proteoglycan (HSPG). In a modality Or preferred, the therapeutic compound inhibits an interaction between a peptide of Aβ and GAG. Consensus binding site motifs for GAG in amyloidogenic protein have been described (see, for example, Hileman R.E. et al. (1998) BioEssays 20: 156-167). For example, a reason for union of The GAG consensus may be of the general formula X-B-B-X-B-X or X-B-B-B-X-X-B-X, where B are basic amino acids (for example lysine or arginine) and X are hydropathic amino acids. A GAG consensus binding motif can be in addition to the general formula T-X-X-B-X-X-T-B-X-X-X-T-B-B-, where T defines 20 a turn of a basic amino acid, Bs are basic amino acids (for example, lysine, arginine, or possibly glutamine) and X are hydropathic amino acids. The distance between the first round and the second round can be within a range of approximately 12Á to 17Á. Distance 25 between the second round and the third round may be approximately 14Á. The distance between the first round and the third round can be located within a range of approximately 13Á to 18Á. More recently, it has been shown that the GAG binding site domain of Aβ (ie, the 13-16: HHQK region) is responsible for the adhesion of Aβ on the surface of microglycels cells leading to its activation (D Guilian, JBC 1998). These results support the "notion" that interference in Aß adhesion by blocking its specific GAG binding site Will he abolish the death of neuronal cells by Aß. Accordingly, in the Aβ interferers of the invention, when multiple anionic groups are fixed on a carrier group, the relative spacing of the anionic groups can be selected such that the anionic groups ( For example, sulfonates or phosphonates) interact optimally with the basic residues within the GAG binding site (thereby inhibiting the interaction of GAG with the site). For example, anionic groups may have a spacing of approximately 15 ± 1.5 A, 14 ± 1.5 A and / or 16 ± 20A, or else appropriate multiples thereof, such that the relative spacing of the anionic groups allows optimal interaction with a binding site for a base membrane constituent (eg, GAG) in an Aβ peptide. 25 Preferably, a p75 receiver interferer of the invention can block a ligand binding site at the p75 receptor, can compete with the natural ligand for binding to the p75 receptor, or it can block the site of ^^ p75 receptor binding in the natural ligand. In addition, an Aβ interferer or p75 receptor interferer of the present invention typically further comprises a counter cation (ie, X + in the general formula: Q - [- Y ~ X +] n). Cationic groups include positively charged atoms and positively charged portions. If the cationic group is? M) hydrogen, H +, then the compound is considered an acid, for example, ethanesulfonic acid. If the hydrogen is replaced by a metal or its equivalent, the compound is a salt of the acid. Pharmaceutically acceptable salts of the Aβ interfering or p75 receptor interfering 15 are within the scope of the present invention. For example, X + may be a pharmaceutically alkaline metal, an alkaline earth, a higher valence cation, a polycationic or ammonium counter ion. A preferred pharmaceutically acceptable salt is a sodium salt but other salts are 20 also contemplate within their pharmaceutically acceptable range. Within the Aβ interferer or p75 receptor interferer, the anionic group (s) is / are covalently linked to a carrier group. Suitable vehicle groups include 25 aliphatic groups, alicyclic groups, heterocyclic groups, aromatic groups, and groups derived from carbohydrates, polymers, peptides, peptide derivatives, or combinations thereof. A carrier group may be substituted, for example, with one or more amino, nitro, halogen, tyl or hydroxyl groups. As used herein, the term "carbohydrate" is intended to include substituted and unsubstituted monosaccharides, oligosaccharides and polysaccharides. Monosaccharides are simple sugars usually of the formula C6H? 206 that can be combined to form oligosaccharides or polysaccharides. Monosaccharides include enantiomers of both the D and L stereoisomers of monosaccharides. Carbohydrates can have multiple anionic groups attached to each portion of monosaccharide. For example, in sucrose octasulfate, four sulfate groups are attached to each of the two monosaccharide moieties. As used herein, the term "polymers" is intended to include molecules formed by the chemical bonding of two or more combination subunits that are known as monomers. Monomers are molecules or compounds that usually contain carbon and have a relatively low molecular weight and a simple structure. A monomer can be converted into a polymer by its combination with the same or with other molecules or similar compounds. A polymer can be composed of a single subunit identical repeating or several different repetitive subunits (copolymers). Polymers within the scope of the present invention include polymers and copolymers of vinyl, acryl, styrene and substituted and unsubstituted carbohydrate derivatives as well as salts thereof. In one embodiment, the polymer has a molecular weight of about 800-1000 daltons. Examples of polymers with covalently-bonded anionic groups (for example, sulfonates or sulfates) include poly (2- ^ iO-acrylamido-2-methyl-l-propanesulfonic acid); poly (2-acrylamido-2-methyl-1-propanesulfonic acid-co-acrylonitrile); poly (2-acrylamido-2-methyl-l-propanesulfonic acid-co-styrene); poly (vinylsulfonic acid), poly (sodium 4-styrenesulfonic acid), and sulfates and / or sulfonates derived from poly (acrylic acid); poly (methyl acrylate); poly (methyl methacrylate); and poly (vinyl alcohol); and pharmaceutically acceptable salts thereof. Examples of polymers with covalently-bonded anionic groups include those of the formula: where R is S03H or 0S0H; and pharmaceutically acceptable salts thereof.

Peptides and peptide derivatives can also act as barriers. The term "peptide" includes two or more amino acids covalently linked through a peptide bond. The amino acids that can be employed in a peptide vehicle include the naturally occurring amino acids that are found in proteins such as glycine, alanine, valine, cysteine, leucine, isoleucine, serine, threonine, methionine, glutamic acid, aspartic acid, glutamine, asparagine , lysine, arginine, proline, histidine, phenylalanine, tyrosine, and tryptophan. The term "amino acid" further includes analogs, derivatives and congeners of naturally occurring amino acids, one or more of which may be present in a peptide derivative. For example, amino acid analogs may have elongated or shortened side chains or side chains. changed with appropriate functional groups. Also included are the stereoisomers D and L of an amino acid when the structure of the amino acid supports the stereoisomeric forms. The term "peptide derivative" further includes compounds that contain molecules that mimic a peptide structure but are not amino acids (those which are known as mimetic peptides), such as benzodiazepine molecules (see, for example, James, GL et al. (1993) Science 260: 1937-1942). The anionic groups can be linked to a peptide or peptide derivative through a functional group in the side chain of certain amino acids or another suitable functional group. For example, a sulfate group may be attached through the hydroxyl side chain of a serine residue. A peptide may be designed to interact with a binding site for a base membrane constituent (eg, a GAG) on an Aβ peptide (in accordance with that described above). Accordingly, in one embodiment, the peptide comprises four amino acids and anionic groups (eg, sulfonate) are fixed on the first amino acid, on the second amino acid and on the fourth amino acid. For example, the peptide can be Ser-Ser-Y-Ser, where an anionic group is fixed on the side chain of each serine residue and Y is any amino acid. In addition to peptides and peptide derivatives, single amino acids can be used as carriers in the Aβ interferent or as the p75 receptor interferer of the invention. For example, cysteic acid, the sulfonate derivative of cysteine, can be used. The term "aliphatic group" is intended to include organic compounds characterized by side or branched chains, typically having between 1 and 22 carbon atoms. The aliphatic groups include alkyl groups, alkenyl groups, and alkynyl groups. In complex structures. The chains may be branched or crosslinked. Alkyl groups include saturated hydrocarbons which include one or more carbon atoms, including straight chain alkyl groups and branched chain alkyl groups. Such hydrocarbon portions may be substituted on one or several carbon atoms for example with a halogen, a hydroxyl, a thiol, an amino, an alkoxy, an alkoxycarboxy, an alkylthio, or a nitro group. Unless the number of carbons is otherwise specified, the term "lower aliphatic" as used herein refers to an aliphatic group, as defined above (for example, lower alkyl, lower alkenyl, lower alkynyl) , but having 1 to 6 carbon atoms. Representative examples of such lower aliphatic groups such as, for example, lower alkyl groups, are methyl, ethyl, n-propyl, isopropyl, 2-chloropropyl, n-5-butyl, sec-butyl, 2-aminobutyl, isobutyl, tert-butyl, - thiopentyl, and the like. As used herein, the term "amino" means -NH2; the term "nitro" indicates -N02; the term "halogen" indicates -F, -Cl, -Br or -I; the term "thiol" means SH; and the term "hydroxyl" refers to -0 OH. Thus, the term "alkylamino" as used herein means -NHR, wherein R is an alkyl group in accordance with that defined above. The term "alkylthio" refers to -SR, wherein R is an alkyl group in accordance with that defined above. The term "alkylcarboxyl" as used herein means -COOR, wherein R is an alkyl group of compliance with what is defined above. The term "alkoxy" as used herein means -OR, wherein R is an alkyl group in accordance with that defined above. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like. The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous to alkyls, but containing at least one double bond or triple bond, respectively. The term "alicyclic group" includes closed ring structures of three or more carbon atoms. Alicylic groups include cycloparaffins or naphthenes which are saturated cyclic hydrocarbons, cycloolefins with two or more double bonds, and cycloacetylenes with a triple bond. They do not include aromatic groups. Examples of cycloparaffins include cyclopropane, cyclohexane, and cyclopentane. Examples of cycloolefins include cyclopentadiene and cyclooctatetraene. Alicyclic groups also include fused ring structures as well as substituted alicyclic groups such as alkyl substituted alicyclic groups. In the case of alicyclics, such substituents may further comprise a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkylthio, a lower alkylamino, a lower alkylcarboxyl, a nitro, a hydroxyl, -CF3, -CN, or the like . The term "heterocyclic group" has the purpose of include closed ring structures in which one or more of the atoms in the ring is an element other than carbon, for example, nitrogen or oxygen. Heterocyclic groups can be saturated or unsaturated and heterocyclic groups such as pyrrole and furan can have an aromatic character. They include fused ring structures such as quinoline and isoquinoline. Other examples of heterocyclic groups include pyridine and purine. Heterocyclic groups can also be substituted on one or several constituent atoms for example with a halogen, a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkylthio, a lower alkylamino, a lower alkylcarboxyl, a nitro, a hydroxyl, -CF3 , -CN, or similar. The term "aromatic group" is intended to include unsaturated cyclic hydrocarbons that contain one or more rings. Aromatic groups include unique 5 and 6 membered ring groups which may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and similar. The aromatic ring can be substituted in one or more ring positions for example with a halogen, a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkylthio, a lower alkylamino, an alkylcarboxyl lower, a nitro, a hydroxyl, -CF3, -CN, or the like. In a preferred embodiment of the method of the invention, the interfering Aβ has administered the subject consists of at least one sulfonate group covalently linked with a carrier group, or a pharmaceutically acceptable salt thereof. Therefore, the interferer of Aß or a receiver interferer p75 can have the structure: Q - [- S03"X +] n where Q is a vehicle group, X + is a cationic group, and n is a whole number. Suitable cationic groups are those described above The number of sulfonate groups ("n") is selected such that the biodistribution of the compound to a predicted target site is not impeded while maintaining the activity of the compound in accordance with that discussed above. In one embodiment, n is an integer between 1 and 10. In another embodiment, n is an integer between 3 and 8. As described above, an Aβ interferer or a p75 receptor interferer with multiple sulfonate groups may having the sulfonate groups spaced such that the compound interacts optimally with an HSPG binding site within the Aβ peptide In preferred embodiments, the sulfonate carrier group (s) is an aliphatic group lower ico (for example, a lower alkyl, lower alkenyl or lower alkynyl), a heterocyclic group and a group derived from a disaccharide, a polymer or a peptide or peptide derivative. In addition, the vehicle may be substituted, for example, with one or • various amino, nitro, halogen, sulfhydryl or 5-hydroxyl groups. In some embodiments, the vehicle for sulfonate (s) is an aromatic group. Examples of suitable sulfonated polymeric .Aβ interferers include poly (2-acrylamido-2-methyl-1-propanesulfonic acid); poly (2-acrylamido-2-methyl-l-0-propanesulfonic acid-co-acrylonitrile); poly (2-acrylamido-2-methyl-1-propanesulfonic acid-co-styrene); poly (vinylsulfonic acid); poly (sodium 4-styrenesulfonic acid); a sulfonic acid derivative of poly (acrylic acid); a poly (methyl acrylate) sulfonic acid derivative; a 15 derivative of poly (methyl methacrylate) sulfonic acid; and a polyvinyl alcohol sulfonate derivative; and pharmaceutically acceptable salts thereof. A preferred sulfonated polymer is poly (vinylsulfonic acid) (PVS) or a pharmaceutically acceptable salt thereof, of Preferably the sodium salt thereof. In one embodiment, PVS having a molecular weight of about 800 to 1000 Daltons is used. PVS can be used in the form of a mixture of stereoisomers or as a single active isomer. Preferred sulfonated saccharides include 5-deoxy-1,2-isopropylidene-alpha-D-xylofurans-5-sulfonic acid (XXIII, shown as the sodium salt). Preferred lower aliphatic sulfonated Aβ interferers for use in the present invention include ethanesulfonic acid; 2-aminoethanesulfonic acid (taurine); cysteic acid (3-sulfoalanine or alpha-amino-β-sulfopropionic acid); 1-propanesulfonic acid; 1,2-ethanedisulfonic acid; 1,3-propandisulfonic acid; 1,4-butanedisulfonic acid; 1, 5-pentand? sulfonic acid; and 4-hydroxybutan-1-sulfonic acid (VIII, shown as the sodium salt); and pharmaceutically acceptable salts thereof. Other aliphatic sulphonated Aβ interferers contemplated for use in the invention include 1-butanesulfonic acid (XLVII, shown as the sodium salt), 2-propanesulfonic acid (XLIX, shown as the sodium salt), 3-pentanesulfonic acid (L, shown as the sodium salt), 4-heptanesulfonic acid (LII, shown as the sodium salt), 1-decansulfonic acid (XLVIII, shown as the sodium salt), and pharmaceutically acceptable salts thereof. Interferers of Aliphatic sulphonated substituted aliphatics contemplated for use in the invention include 3-amino-1-propanesulfonic acid (XXII, shown as the sodium salt), 3-hydroxy-1-propanesulfonic acid sulfate (XXXV, shown as the disodium salt), 1,7-dihydroxy-4-heptanesulfonic acid (Lili, shown as the sodium salt), and pharmaceutically acceptable salts thereof. Other sulfonated compounds contemplated for use in the invention include 2- [(4-pyridinyl) amido] ethanesulfonic acid (LIV, represented as the sodium salt), and pharmaceutically acceptable salts thereof.

Preferred heterocyclic sulphonated Aβ interfering agents include 3- (N-morpholino) -1-propanesulfonic acid; and tetrahydrothiophen-1, l-dioxide-3,4-disulfonic acid; and pharmaceutically acceptable salts thereof. Interfering sulfur aromatic Aβs include 1,3-benzenedisulfonic acid (XXXVI, illustrated as the disodium salt), 2, 5-dimethoxy-1, 4-benzenedisulfonic acid (illustrated as the disodium salt, XXXVII, or the dipotassium salt, XXXIX), 4-amino-3-hydroxy-1-naphthalenesulfonic acid (XLIII), acid 3, 4- diamino-1-naphthalenesulfonic acid (XLIV); and pharmaceutically acceptable salts thereof. In another embodiment of the method of the invention, the Aβ interferer administered to the subject consists of at least one sulfate group covalently linked to a carrier group, or a pharmaceutically acceptable salt thereof. As a result, the Aß interferer or the p75 receiver interferer can 20 having the structure: Q - [- OS03"X +] n where Q is a vehicle group, X + is a cationic group, and n is an integer, Suitable cationic vehicles and groups are those described above, The number of sulfate groups (". n ") 25 is selected in such a way that the biodistribution of the compound for a predicted target site is not impeded while maintaining the activity of the Aß interferer in accordance with the above. In one modality, n is a • whole number between 1 and 10. In another mode, n is an integer number between 3 and 8. In accordance with what is described above, an interferent of A £ > with multiple sulfate groups may have the sulfate groups spaced such that the compound interacts optimally with a GAG binding site within an Aβ peptide. In preferred embodiments, the carrier group for sulfate (s) is a lower aliphatic group (eg, a lower alkyl, lower alkenyl or lower alkynyl), an aromatic group, a group derived from a disaccharide, a polymer or a peptide or peptide derivative. In addition, the The vehicle can be substituted, for example, with one or more amino, nitro, halogen, sulfhydryl or hydroxyl groups. Examples of suitable sulfated polymeric Aβ interferers or suitable p75 receptor interferers include Poly (2-acrylamido-2-methyl-propylsulfuric acid); poly (2-acrylamido-2-methyl-propylsulfuric acid-co-acrylonitrile); poly (2-acrylamido-2-methyl-propylsulfuric acid-co-styrene); poly (vinylsulfuric acid); poly (sodium 4-styrenesulfate); a polyacrylic acid sulfate derivative; a derivative 25 of poly (methyl acrylate) sulfate; a derivative of poly (methyl methacrylate) sulfate; and a polyvinyl alcohol sulfate derivative; and pharmaceutically acceptable salts thereof. A preferred sulfated polymer is poly (vinylsulfuric acid) or a pharmaceutically acceptable salt thereof. A preferred sulfated disaccharide is sucrose octasulfate or a pharmaceutically acceptable salt thereof. Other sulfated saccharides contemplated for use in the invention include the acid form of 2,3-disulphate methyl-alpha-D-glucopyranoside (XVI), 2,3-disulfate-4-benzylidene-alpha-D methylglycopyranoside (XVII), 2,3,4,3 ', 4'-sucrose pentasulfate (XXXIII), 3,5-disulfate 2,3: 4,6-di-0-benzylidene-D-mannitol (XLI); 2, 5-D-mannitol disulfate (XLII), 2,5-di-O-benzyl-D-mannitol tetrasulfate (XLV); and pharmaceutically acceptable salts thereof. Preferred lower aliphatic sulfated Aβ interferers for use in the present invention include ethylsulfuric acid; 2-aminoethane-l-ol sulfuric acid; 1-propanol sulfuric acid; 1,2-ethanediol disulfuric acid; 1,3-propanediol disulphuric acid; 1,4-butanediol disulphuric acid; 1, 5-pentanediol disulfuric acid; and 1,4-butanediol monosulfuric acid; and pharmaceutically acceptable salts thereof. Other sulfated aliphatic Aβ interferers contemplated for use in the present invention include the disulfate acid form of 1,3-cyclohexanediol (XL), 1, 3, 5-heptantriol trisulfate (XIX), 2-hydroxymethyl-1,3-propandiol trisulfate (XX), 2-hydroxymethyl-2-methyl-l, 3-propanediol trisulfate (XXI), tetrasulfate 1 , 3, 5, 7-heptantetraol (XLVI), 1,3,5,7,9-nonane pentasulfate (Ll); and pharmaceutically acceptable salts thereof. Other sulfated Aβ interferers contemplated for use in the present invention include the trisulfate acid form of 2-amino-2-hydroxymethyl-l, 3-propanediol (XXIV), 2-benzyloxy-l, 3-propanediol disulfate ( XXIX), 3-hydroxypropylsulfamic acid sulfate (XXX), 2,2'-iminoethanol disulfate (XXXI), N, -bis (2-hydroxyethyl) sulfamic acid disulfate (XXXII); and pharmaceutically acceptable salts thereof. Preferred heterocyclic sulfated Aβ interferers include sulfuric acid. 3- (N-morpholino) -1-propyl; and disulfuric acid of tetrahydrothiophen-3,4-diol-1,1-dioxide; and pharmaceutically acceptable salts thereof. The invention further encompasses the use of prodrugs converted in vivo into the Aβ interferers employed in the methods of the invention (see, for example, RB Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action", Academic Press, chapter 8). Such prodrugs can be used to alter the biodistribution (e.g., to allow compound that typically does not cross the blood-brain barrier to pass through said barrier hematoencephalic) or the pharmacokinetic characteristics of the Aß interfering. For example, an anionic group such as for example a sulfate or a sulfonate, can be esterified, for example with a methyl group or a phenyl group to provide a sulfate or sulfonate ester. When the sulfate sulfonate ester is administered to a subject, the ester is dissociated, enzymatically or non-enzymatically, in a reductive or hydrolytic manner, to reveal the anionic group. Said ester may be cyclic, for example, cyclic sulfate or cyclic sultone, or two or more anionic portions may be esterified through a linking group. Exemplary cyclic Aβ interferers include, for example, 2-sulfobenzoic acid (LV) cyclic anhydride, 1, 3-propansultone (LVI), 1,4-butansultone (LVII), 1,3-butanediol cyclic sulfate (LVIII) , gamma-sultone of alpha-chloro-alpha-hydroxy-o-toluenesulfonic acid (LIX), and 2,2-dioxide of 6-nitronaft- [1,8-cd] -1,2-oxathiol (LX). In a preferred embodiment, the prodrug is a cyclic sulfate or a cyclic sultone. An anionic group may be esterified with dissociated portions (e.g., acyloxymethyl esters) to reveal an intermediate Aβ interfering which subsequently decomposes to provide the active Aβ interfering. In another embodiment, the prodrug is a reduced form of a sulfate or sulfonate, for example, a thiol oxidized in vitro in the interferente of Aß. In addition, an anionic portion may be esterified in a group actively transported in vivo, or selectively absorbed by the target organs. He ^ F ester may be selected to allow a specific approach of the Aβ interferers to particular organs, in accordance with what is described below for the vehicle portions. Vehicle groups useful in the Aβ interferers include previously described groups, for example aliphatic αβ Q groups, alicyclic groups, rocyclic groups, aromatic groups, carbohydrate derived groups, polymers, peptides, peptide derivatives, or combinations thereof. Suitable polymers include polymers and copolymers of vinyl, acryl, styrene and carbohydrate derivatives 15 substituted and unsubstituted as well as salts thereof. Preferred carrier groups include a lower alkyl group, a rocyclic group, a group derived from a disaccharide, a polymer, a peptide or a peptide derivative. Vehicle groups useful in the present invention may 20 also include portions that allow the Aβ interferent to be selectively delivered to a target organ or target organs. For example, if the administration of an interferer of t? S > to the brain is desired, the vehicle group may include a portion capable of directing the interfering 25 Aß to the brain, either by active transport or passive (a "focus portion"). Illustratively, the carrier group may include a redox portion, in accordance with that described for example in U.S. Patent Nos. 4,540,564 and 5,389,623, both to Bodor. These patents disclose drugs attached to portions of dihydropyridine that can penetrate the brain where they are oxidized in a kind of charged pyridinium that is trapped in the brain. Thus, the drug accumulates in the brain. Exemplary pyridine / dihydropyridine compounds of the present invention include sodium 2- (nicotinylamido) -ethansulfonate (LXII), and 1- (3-sulfopropyl) -pyridinium betaine (LXIII). Other vehicle portions include groups such as amino acid derivatives or thyroxine which can be transported passively or actively in vivo. An illustrative compound is phenylalanyltaurine (LXIX) wherein a molecule of taurine is conjugated to a phenylalanine (a large neutral amino acid). A portion of this type of vehicle can be removed metabolically in vivo, or it can remain intact as part of an active Aβ interfering agent. Structural amino acid mimetics (and other actively transported portions) are also useful in the invention (eg, 1- (aminomethyl) -1- (sulfomethyl) -cciohexane (LXX)). Other exemplary amino acid mimetics include p- (sulfomethyl) phenylalanine (LXXII), p- (1,3-disulfoprop-2-) il) phenylalanine (LXXIII), and O- (1,3-disulfoprop-2-yl) tyrosine (LXXIV). Exemplary thyroxine mimetics include compounds LXXV, LXVI, and LXXVII. Many portions are known • of focus which include, for example, asialoglycoproteins (see, for example, US Patent No. 5,166,320 to Wu) and other ligands that are transported into cells through receptor-mediated endocytosis (see below for additional examples of focusing portions that can be covalently or non-covalently bound on a carrier molecule). In addition, the Aβ interferers of the present invention can be linked with amyloidogenic proteins, for example, Aβ peptide, in the circulation and therefore be transported to the site of action. The targeting and prodrug strategies described above can be combined to produce an Aβ interfering that can be transported as a prodrug to a desired action site and then unmasked to reveal an active Aβ interfering. For example, the strategy of Bodor dihydropyrin (see above) can be combined with a cyclic prodrug as for example in the compound 2- (1-methyl-1,4-dihydronicotinyl) amidomethyl-propansultone (LXXI). In one embodiment, the Aβ interferer in the pharmaceutical compositions is a sulfonated polymer, for example, 25 poly (2-acrylamido-2-methyl-l-propanesulfonic acid); poly (2-acrylamido-2-methyl-l-propanesulfonic acid-co-acrylonitrile); poly (2-acrylamido-2-methyl-l-propanesulfonic acid-co-styrene); poly (vinylsulfonic acid); poly (sodium 4-styrenesulfonic acid); a poly (acrylic acid) sulfonate derivative; a poly (methyl acrylate) sulfonate derivative; a poly (methyl methacrylate) sulfonate derivative; and a polyvinyl alcohol sulfonate derivative; and pharmaceutically acceptable salts thereof. In another embodiment, the Aβ interferer in the pharmaceutical compositions is a sulfated polymer, for example, poly (2-acrylamido-2-methyl-1-propylsulfuric acid); poly (2-acrylamido-2-methyl-l-propylsulfuric acid-co-acrylonitrile); poly (2-acrylamido-2-methyl-1-propylsulfuric acid-co-styrene); poly (vinylsulfuric acid), poly (sodium 4-styrenesulfate); a derivative of poly (acrylic acid) sulfate; a poly (methyl acrylate) sulfate derivative; a poly (methyl methacrylate) sulfate derivative; and pharmaceutically acceptable salts thereof. The interferer of Aß or interferer of receiver p75 can also have the structure: (CY1Y2) nC (X) XR3 RX wherein Z is XR2 or R4, R1 and R2 are each independently hydrogen, a substituted or unsubstituted aliphatic group (preferably a straight or branched chain aliphatic portion having from 1 to 24 carbon atoms in the chain, or a unsubstituted or substituted cyclic aliphatic portion having from 4 to 7 carbon atoms in the aliphatic ring, preferred cyclic aliphatic and aliphatic groups are alkyl groups, more preferably lower alkyl), an aryl group, a heterocyclic group, or a cation salt formation; R3 is hydrogen, lower alkyl, aryl or a salt formation cation; X is, independently for each case, 0 or S; R 4 is hydrogen, lower alkyl, aryl or amino; Y1 and Y2 are each independently hydrogen, halogen, (eg, F, Cl, Br, or I), lower alkyl, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), hydroxy, alkoxy, or aryloxy; and n is an integer from 0 to 12 (more preferably from 0 to 6, especially 0 or 1); in such a way that the amyloid deposit is modulated. These compounds are described in the North American Application No. of Series 08 / 912,574, whose contents are incorporated herein by reference. Preferred Aβ interferers or preferred p75 receptor interferers for use in the invention include compounds in which both R1 and R ~ are cations that form pharmaceutically acceptable salts. It will be noted that the stoichiometry between an anionic compound and a salt formation counter ion (optionally) varies depending on the charge of the anionic portion of the compound (optionally) and the charge of the counterion. In a particularly preferred embodiment, R1, R2 and R3 are each, independently, a sodium, potassium or calcium cation. In certain embodiments in which at least one of R1 and R2 is an aliphatic group, the aliphatic group has between 1 and 10 carbon atoms in the straight or branched chain, and is more preferably a lower alkyl group. In other embodiments in which at least one of R1 and R2 is an aliphatic group, the aliphatic group has between 10 and 24 carbon atoms in the straight or branched chain. In certain preferred embodiments, n is 0 or 1; more preferably, n is 0. In certain preferred embodiments of the therapeutic compounds, Y1 and Y2 are each hydrogen. In certain preferred embodiments, the Aβ interferer or p75 interferer of the present invention may have the structure: X (CY1Y2) nC (0) 0R3 • RX XR 'where R1, R2, R3, Y1, Y2, X and n are in accordance with what is defined above. In more preferred embodiments, the Aβ interferer or p75 receiver interferer of the present invention may have the structure: X (CYXY2) pCH (NRaRb) C (O) OR3 RxO OR¿ 15 wherein R1, R2, R3, Y1, Y2, and X are in accordance with the above defined, Ra and Rb are, each independently, hydrogen, alkyl , aryl, or heterocyclyl, or Ra and Rb, together with the nitrogen atom on which they are attached, form a cyclic portion having 3 to 8 atoms 20 in the ring and n is an integer from 0 to 6. In certain preferred embodiments, Ra and Rb are each hydrogen. In certain preferred embodiments, a compound of the invention comprises an alpha-amino acid (or alpha-amino acid ester), more preferably an L-alpha-amino acid or 25 ester.

The groups Z, R1, R2, R3, Y1, Y2 and X are, each independently, selected in such a way that the biodistribution of the Aβ interferent or p75 receptor interferer for a predicted target site is not impeded while maintaining the interference activity of Aß or interferer of receiver p75. For example, the number of anionic groups (and the overall load on the therapeutic compound) must not be so great that an anatomical barrier, such as a cell membrane, or entry through a physiological barrier is prevented. , as for example, the blood-brain barrier, in situations in which such properties are desired. For example, it has been reported that phosphonoformate esters have different biodistribution properties and in some cases superior to the biodistribution properties of phosphonoformate (see, for example, U.S. Patent Nos. 4,386,081 and 4,591,583 to Helgstrand et al., And Patents North American Nos. 5,194,654 and 5,463,092 of Hostetler et al.). Thus, in certain embodiments, at least one of R1 and R2 is an aliphatic group (more preferably an alkyl group), wherein the aliphatic group has between 10 and 24 carbon atoms in the straight or branched chain. The number, length, and degree of branching of the aliphatic chains can be selected to provide a desired characteristic, for example, lipophilicity. In other embodiments, at least one of R1 and R2 is an aliphatic group (more preferably an alkyl group), wherein the aliphatic group has between 1 and 10 carbon atoms in the straight or branched chain. Again, the number, length and degree of branching may be selected to provide a desired characteristic such as, for example, lipophilicity or ease of ester dissociation by enzymes. In certain embodiments, a preferred aliphatic group is an ethyl group. In another embodiment, the Aβ interferer or p75 receiver interferer of the invention may have the structure: wherein G represents hydrogen or one or more substituents on the aryl ring (eg, alkyl, aryl, halogen, amino, and the like) and L is a substituted alkyl group (in certain embodiments, preferably lower alkyl), more preferably an alkyl substituted by hydroxy or an alkyl substituted with a nucleoside base. In certain embodiments, G is hydrogen or an electron donor group. In modalities in which G is a group of Withdrawal of electrons, G is preferably an electron withdrawing group in the meta position. The term "electron withdrawing group" is known in the art and, as used herein, refers to a group that has a removal of electrons greater than hydrogen. Many electron withdrawing groups are known which include halogens (eg, fluorine, chlorine, bromine, and iodine groups), nitro, cyano, and the like. Similarly, the term "electron donor group", as used herein, refers to a group that is less electron withdrawing than hydrogen. In embodiments in which G is an electron donor group, G can be found in the ortho, meta or para position. In certain preferred embodiments, L is a portion selected from the group consisting of: Table 1 presents a list of pertinent data for the characterization of these compounds using known techniques. The compounds IVa-IVg in Table 1 correspond to the following structure, where L is a group selected from the compounds listed above (groups IVa-IVg) with the same number.

Table 1 COMPOSITE 31 LPt NMR 13C NMR IVa -6.33 (DMSO-d6) 60.97 CH2OH (d, J = 6Hz) 66.76 CHOH (d, J = 7.8Hz) 121.65, 121.78, 121.99, 125.71, 129.48, 129.57, 126.43 CH aromatic 134.38 Aniline CN 150.39 phenyl C-0 (d, J = 7Hz) 171.57 PC = 0 (d, J = 234Hz) IVb -6.41 (DMSO-de) 13.94 CH3 22.11, 24.40, 28.56, 28.72 28.99, 29.00, 31.30, 33.43 - (CH :)? O- 65.03 CH2-OC (O) 66.60 CH2-OP (d, J = 5.6Hz) 67.71 CH2-OH (d, J = 6 Hz) 121.73, 121.10, 125.64, 5 126.57, 129.40, 129.95, aromatic CH 134.04 aniline CN 150.31 phenyl CO 171.44 PC = 0 (d, J = 6.7 Hz)? 0 172.83 0-C = 0 IVc -6.46 (DMS0-d6) 13.94 CH3 22.11, 25.10, 28.68, 28.72 28.85, 29.00 , 30.76, 31.31 32.10, 15 - (CH2)? O- 43.36 CH2-S 68.43 CH2-OH f 68.43 CH-OH (d, J = 6.3 Hz) 68.76 P-0-CH2-9d, J = 5.8 Hz) 20 121.75, 122.03, 125.62, 126.37, 129.30, 129.53, aromatic CH 134.23 aniline C.N 150.37 phenyl C-0 (d, J = 6.7 25 'Hz) 171. 47 PC = 0 (d, J = 234.0 Hz) 198.47 SC = 0 IVd -6.61 (DMSO-de) 13.94 CH3 22.06, 25.14, 28.24, 28.35 31.09, 32.14 -CH2) 6- 43.40 CH2-S 68.50 P-0- CH2- (d, J = 5.8 Hz) 68.77 CH-OH (d, 6.4 Hz) 121.78, 122.59, 125.69, 127.06, 129.43, 129.59 aromatic CH 133.39 aniline CN 150.38 phenyl C-0 (d, J = 6.7 Hz) 171.47 PC = 0 (d, J = 234.4 Hz) 198.54 SC = 0 IVe -5.76 (D20) N / A IVf, -7.00 (DMSO-de) N / A IVg -6.60 (DMSO-D6) 70.84 CH2-OH 72.17 CH -OH 121.68, 121.79, 121.85, 125.71, 127.10, 127.92, 129. 36, 129.50, 129.59 aromatic CH 134.51 aniline C-N • 142.34 aromatic C-CH 5 150.37 phenyl C-0 (d, J = 6.2 Hz) 171.59 P-C = 0 (d, J = 232.6 Hz) COMPOSITE FAB-MS (-) IVa 245.2 IVb 456 IVc 471 IVd 416 IVe N / A IVf N / A 15 IVg 321 An anionic group (ie a phosphonate or carboxylate group) of an Aβ interfering agent or a p75 receptor interferer of the invention is a negatively charged portion which, in certain preferred embodiments, can modulate the interaction between a peptide Aβ and a component of a base membrane, eg, GAG or the p75 receptor to modulate eg the formation of fibrils of Aß or cell death. It will be noted that the structure of some of the 25 interferers of Aβ or interferers of the p75 receiver of this invention include asymmetric carbon atoms. It will be understood, therefore, that isomers (e.g., enantiomers and diastereomers) arising from such asymmetry are included within the scope of the invention. Such isomers can be obtained in substantially pure form by classical separation techniques and by sterically controlled synthesis. For purposes of this invention, unless otherwise expressly indicated, an Aβ interfering or a p75 receptor interfering should be considered as including both the R or S stereoisomers at each chiral center. In certain embodiments, an Aβ interferer or a p75 receptor interferer of the present invention comprises a cation, (ie, in certain embodiments, at least one of R1, R2 or R3 is a cation). If the cationic group is hydrogen, H +, then the Aβ interferent or p75 receptor interferer is considered an acid, for example, phosphonoformic acid. If hydrogen is replaced by a metal ion or its equivalent, the interfering Aβ or interfering p75 receptor is a salt of the acid. Pharmaceutically acceptable salts of the Aβ interferer or p75 receptor interferer are within the scope of the invention. For example, at least one of R1, R2 or R3 may be a pharmaceutically acceptable alkali metal (eg, Li, Na, or K), ammonium cation, earth cation alkaline (eg, Ca2 +, Ba2 +, Mg2 *), higher valence cation, or polycationic counterion (eg, polyammonium cation). (See, for example, Berge et al., (1977) • "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19). It will be observed that the stoichiometry between an anionic compound and a salt formation counterion (optionally) varies depending on the charge of the anionic portion of the compound (optionally) and the charge of the counterion. Preferred pharmaceutically acceptable salts include a sodium, potassium or calcium salt, but ij? other salts are also contemplated within their pharmaceutically acceptable range. The term "pharmaceutically acceptable esters" refers to the relatively non-toxic esterified products of the Aβ interferers or the p75 receptor interferers of the 15 present invention. These esters can be prepared in situ during the final isolation and purification of the Aβ interferers or p75 receptor interferers, or by the separate reaction of the purified or purified Aβ interfering intercept of purified p75 receptor in its Free acid form or hydroxyl with a suitable esterification agent; Any methods are known to those skilled in the art. Carboxylic acids and phosphonic acids can be converted into esters in accordance with well-known methods by a 25 person with normal knowledge in the art, for example, by treatment with an alcohol in the presence of a catalyst. A preferred ester group (for example, when R3 is lower alkyl) is an ethyl ester group. The term "alkyl" refers to saturated aliphatic groups, including straight chain alkyl groups, branched chain alkyl groups, cycloalkyl (alicyclic) groups, cycloalkyl groups substituted by alkyl, and alkyl groups substituted by cycloalkyl. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its structure (eg, C? -C3o for straight chain, C-C30 for branched chain) and more preferably 20 or less. In the same way, preferred cycloalkyls have from 4 to 10 carbon atoms in their ring structure, and more preferably have from 4 to 7 carbon atoms in the ring structure. The term "lower alkyl" refers to alkyl groups having from 1 to 6 atoms in the chain, and to cycloalkyls having from 3 to 6 carbon atoms in the ring structure. In addition, the term "alkyl" (including "lower alkyl" as used in the specification and in the claims includes both "unsubstituted alkyls" and "substituted alkyls", the latter referring to alkyl portions having substituents that replace a hydrogen in one or several carbon atoms of the hydrocarbon structure, such substituents may include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, 5 cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, or a portion aromatic or heteroaromatic. It will be understood by those skilled in the art that substituted portions in the hydrocarbon chain may be substituted, if appropriate. The Cycloalkyls may be further substituted, for example, with the substituents described above. An "aralkyl" moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)). The term "alkoxy", as used herein, refers to a The portion having the structure -O-alkyl, wherein the alkyl portion is in accordance with that described above. The term "aryl" as used herein includes 5- and 6-membered single ring aromatic groups which may include from zero to four heteroatoms, for example, benzene, 25 pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like unsubstituted or substituted. Aryl groups also include polycyclic fused aromatic groups ^ such as naphthyl, quinolyl, indolyl, and the like. The aromatic ring can be substituted in one or more ring positions with substituents such as those described, for example, above, for the alkyl groups. Preferred aryl groups include substituted and unsubstituted phenyl groups. The term "aryloxy", as used herein, refers to a group having the structure -O-aryl, wherein the aryl portion is in accordance with that defined above. The term "amino", as used herein, refers to an unsubstituted or substituted portion of the formula -NRaRD, in Where Ra and R, each independently, are hydrogen, alkyl, aryl, or heteroaryl, or Ra and Rb together with the nitrogen atom on which they are attached form a cyclic portion having from 3 to 8 ring atoms . Thus, the term "amino" is intended to include 20 cyclic amino moieties such as the piperidinyl or pyrrolidinyl groups, unless otherwise indicated. An "amino group substituted by amino" refers to an amino group in which at least one of Ra and Rb is further substituted with an amino group. In a preferred embodiment, R1 or R2 may be (so less in one case) a long chain aliphatic portion. The term "long chain aliphatic portion" as used herein, refers to a portion having a straight or branched chain aliphatic portion (eg, an alkyl or alkenyl portion) having from 10 to 24 carbon atoms in the aliphatic chain, for example, the long chain aliphatic portion is an aliphatic chain of a fatty acid (preferably a naturally occurring fatty acid). Representative long chain aliphatic portions include the aliphatic chains of stearic acid, oleic acid, linolenic acid, and the like. In certain embodiments, the interferer of .AJi or receiver interferer p75 of the present invention may have the structure: (CYLY2) nCOOR3 OR where R1 and R2 are each independently hydrogen, an aliphatic group (preferably a straight or branched chain aliphatic portion having from 1 to 24 carbon atoms, more preferably from 10 to 24 carbon atoms, in the chain, or a substituted or unsubstituted cyclic aliphatic portion having from 4 to 7 carbon atoms in the aliphatic ring), an aryl group, a heterocyclic group, or a salt formation cation; R3 is hydrogen, lower alkyl, aryl or a salt formation cation; Y1 and Y2 are each independently hydrogen, halogen (eg, F, Cl, Br or I), lower alkyl, hydroxy, alkoxy, or aryloxy; and n is an integer from 0 to 12; in such a way that the amyloid deposit is modulated. In a preferred embodiment, the Aβ interferers or p75 receptor interferers of the present invention prevent or inhibit the deposition of amyloid in a subject to which the Aβ interfering or the p75 receptor interfering is administered. Interfering Aβ or preferred p75 receptor interferers for use in the present invention include compounds in which both R 1 and R * are pharmaceutically acceptable salt formation cations. In a particularly preferred embodiment, R1, R2 and R3 are each, independently, a sodium, potassium or calcium cation, and n is 0. In some preferred embodiments of the therapeutic compounds, Y1 and Y2 are each hydrogen. Preferred Aβ interfering or preferred p75 receptor interferers are phosphonoformate salts. A trisodium phosphonoformate (foscarnet sodium or Foscavir®) is commercially available (for example, from Astra), and its clinical pharmacology has been studied (see, for example, "Physician's Desk Reference", edition 51, pages 541-545 ( 1997)).

In another embodiment, the Aβ interferer or p75 receptor interferer employed in the present invention can be an aminophosphonate, a bisphosphonate, a derivative of • Phosphonocarboxylate, a phosphonate derivative, or a phosphonocarbohydrate. For example, the Aβ interferent or p75 receptor interferer may be one of the compounds described in appended Appendix A. Pharmaceutically acceptable formulations In the method of the invention, the Aβ interferer or p75 receptor interferer can be administered in a • pharmaceutically acceptable formulation. The present invention pertains to any pharmaceutically acceptable formulation such as for example synthetic or natural polymers in the form of macromolecular complexes, nanocapsules, 15 microspheres or beads, and lipid-based formulations that include oil-in-water emulsions, micelles, mixed micelles, synthetic membrane vesicles, as well as erythrocytes • resealed. In one embodiment, pharmaceutically formulations Acceptable include a polymer matrix. The terms "polymer" or "polymeric" are known in the art and include a structure consisting of repeating monomer units that can supply an Aβ interferer or a p75 receptor interferer, such that 25 a treatment of a focused condition occurs, for example, an injury of the central nervous system. The terms also include copolymers and homopolymers, for example, synthetic or natural. Linear polymers, branched polymers, and cross-linked polymers are also included. For example, polymeric materials suitable for the formation of the pharmaceutically acceptable formulation employed in the present invention include naturally derived polymers such as albumin, alginate, cellulose derivatives, collagen, fibrin, gelatin, and polysaccharides, as well as synthetic polymers such as polyesters (PLA, PLGA), polyethylene glycol, poloxomers, polyanhydrides, and pluronics. These polymers are biocompatible with the nervous system, including the central nervous system, are biodegradable within the system Central nervous system without producing toxic byproducts of degradation, and possess the ability to modify the form and duration of interfering release of Aβ or interfering with p75 receptor by manipulating the kinetic characteristics of the polymer. As used here, The term "biodegradable" indicates that the polymer will be degraded over time by the action of enzymes, by hydrolytic action and / or by other similar mechanisms in the patient's body. As used here, the term "biocompatible" means that the 25 polymer is compatible with a living tissue or a living organism because it is not toxic or causes damage or causes immune rejection. The polymers can be prepared using methods known in the art (Sandler, SR, Karo, W. Polymer Syntheses, Harcourt Brace: Boston, 1994, Shalaby, W .; Ikada, Y .; Langer, R.; Williams, J. Polymers. of Biological and Biomedical Significance (ACS Symposium Series 540: American Chemical Society: Washington, DC, 1994) Polymers can be designed to be flexible, the distance between the bioactive side chains and the length of a linker between the polymer structure and the group can be controlled Other suitable polymers and methods for their preparation are described in US Patents Nos. 5,455,044 and 5,576,018, the contents of which are incorporated herein by reference.polymeric formulations are preferably formed by dispersion of the Aβ interferent or receptor interferer p75 within the liquefied polymer, in accordance with that described in U.S. Patent No. 4,883,666, the teachings of which are incorporated herein by Reference, or through methods such as volume polymerization, interfacial polymerization, solution polymerization and ring polymerization according to that described in Odian G., Principles of Polymerization and ring opening polymerization, 2nd. edition, John Wiley & Sons, New York, 1981, whose contents are incorporated here by reference. The properties and characteristics of the formulations are controlled by varying parameters such as reaction temperature, polymer and interfering concentrations of Aβ, or interferer of p75 receptor, solvent types used as well as reaction times. In addition to the Aβ interferent or p75 receptor interferer and the pharmaceutically acceptable polymer, the pharmaceutically acceptable formulation employed in the method of the invention may comprise additional pharmaceutically acceptable carriers and / or excipients. As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents., physiologically compatible absorption and isotonic retardation agents and the like. For example, the vehicle may be suitable for injection into the cerebrospinal fluid. Excipients include pharmaceutically acceptable stabilizers and disintegrants. The Aβ interferer or p75 receptor interferer may be encapsulated in one or more pharmaceutically acceptable polymers to form a microcapsule, microsphere, or microparticle, terms used interchangeably herein. Microcapsules, microspheres, and microparticles are conventionally free-flowing powders which consist of spherical particles of 2 millimeters or less in diameter, usually 500 microns or less in diameter. Particles less than one ore are conventionally known as nanocapsules, nanoparticles or nanospheres. In most cases, the difference between a microcapsule and a nanocapsule, a microsphere and a nanosphere, or a microparticle and a nanoparticle is the size; In general, there is little difference or no difference between the internal structure of the two. In one aspect of this The invention, the average diameter is less than about 45 μm, preferably less than 20 μm, and especially between 0.1 and 10 μm. In another embodiment, pharmaceutically acceptable formulations comprise lipid-based formulations.

Any known lipid-based drug delivery systems may be employed in the practice of the invention. For example, multivesicular liposomes (MVL), multilamellar liposomes (also known as multilamellar vesicles or "MLV"), unilamellar liposomes 20 including small unilamellar liposomes (also known as unilamellar vesicles or "SUV") as well as large unilamellar liposomes (also known as large unilamellar vesicles or "LUV"), can also be used to the extent that a release rate can be established 25 sustained from the interferential Aβ encapsulated or interfering of encapsulated p75 receiver. In one embodiment, the lipid-based formulation can be a multivesicular liposome system. Methods for making multivesicular liposome administration systems of controlled release 5 are described in PCT Nos. Serial Nos. US96 / 11642, US94 / 12957 and US94 / 04490, the contents of which are incorporated herein by reference. The composition of the synthetic membrane vesicle is usually a combination of phospholipids, usually 10 in composition with steroids, especially cholesterol. Other phospholipids and other lipids can also be used. Examples of lipids useful in the production of synthetic membrane vesicles include phosphatidylglycerols, phosphatidylcholines, phosphatidylserines, phosphatidylethanolamines, 15 sphingolipids, cerebrosides, and gangliosides. The phospholipids preferably include egg phosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidyl choline, dioleoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, and dioleoylphosphatylglycerol.

In the preparation of lipid-based vesicles containing an Aβ interferer or p75 receptor interferer, such variables as the efficiency of Aβ interferential encapsulation or p75 receptor interferer, the lability of the Aβ interferent or receptor interferer 25 p75, the homogeneity and size of the population resulting from vesicles, the relationship between interfering Aβ or interfering receptor p75 and lipid, permeability, instability of the preparation, and pharmaceutical acceptability of the formulation should be considered (see, Szoka, et al., Annual Reviews of Biophysics and Bioengineering, 9: 467, 1980, Deamer, et al., In Liposomes, Marcel Dekker, New York, 1983, 27, and Hope, et al., Chem. Phys. Lipids, 40:89, 1986, the contents of which are incorporated herein by reference. Administration of the pharmaceutically acceptable formulation In one embodiment, the Aβ interferent or the p75 receptor interferer is administered by introduction into the central nervous system of the subject, for example, in the subject's cerebro-spinal fluid. invention, the Aβ interferent or the p75 receptor interferer is introduced intrathecally, for example, into the ventricle of the brain, the lumbar area, or the cisterna magna. in being easily suspended in aqueous vehicles and introduced through conventional hypodermic syringes or using infusion pumps. Before the introduction, the formulations can be preferably sterilized with gamma radiation or electron beam sterilization, in accordance with that described in US Pat. No. 436,742, the contents of which are incorporated herein by reference.

In another embodiment of the invention, the interfering Aβ or interfering p75 receptor formulation is administered intrathecally in a subject. As used herein, the term "intrathecal administration" includes administering an Aβ interfering or interfering p75 receptor formulation directly into the brain-spinal fluid of a subject, by techniques including lateral brain-ventricular injection through a cisternal or lumbar orifice or perforation or similar (in accordance with that described in Lazorthes et al Advances in Drug Delivery Systems and Applications in Neurosurgery, 143-192 and Omaya et al., Cancer Drug Delivery, 1: 169-179, whose contents they are incorporated here by reference). The term "lumbar region" includes the area between the third lumbar vertebra and the fourth lumbar vertebra (lower part of the back). The term "cisterna magna" includes the area where the skull ends and where the vertebral spine begins at the back of the head. The term "cerebral ventricle" includes the cavities of the brain that are continuous with the central channel of the spine. The administration of an Aβ interferer or a p75 receptor interferer in any of the aforementioned sites can be achieved by direct injection of the Aβ interfering formulation or p75 receptor interferer or by the use of infusion pumps. For injection, the interfering formulation of Aβ or p75 receptor interferer of the present invention can be formulated in liquid solutions, preferably in physiologically compatible buffers such as Hank's solution or Ringer's solution. In addition, the Aβ interfering or interfering p75 receptor formulation can be formulated in solid form and redissolved or suspended immediately before use. Lyophilized forms are also included. The injection can be, for example, in the form of a bolus injection or by continuous infusion, fclO (for example using infusion pumps) of the Aβ interfering formulation or p75 receptor interferer. Duration and levels of administration In another embodiment of the method of the invention, the pharmaceutically acceptable formulation provides an administration 15 sustained, for example, a "slow release" of the Aβ interferer or p75 receptor interferer to a subject for at least one, two, three or four weeks after administration of the pharmaceutically acceptable formulation to the subject. As used herein, the term "sustained administration" is intended to include the continuous administration of an Aβ interferer or p75 receptor interferer in vivo for a period of time after administration, preferably at least several days, a week or several 25 weeks Sustained administration of the Aß interferent or Interfering p75 receptor can be demonstrated for example by the continuous therapeutic effect of the Aβ interferer or p75 receptor interferer over time (for example, the sustained delivery of the Aβ interferent or p75 receptor interferer can be demonstrated by the continuous inhibition of the death of neuronal cells with the passage of time). Alternatively, sustained delivery of the Aβ interferer or p75 receptor interferer may be demonstrated by detecting the presence of the Aβ interferer or p75 receptor interferer in vivo over time. In one embodiment, the pharmaceutically acceptable formulation provides sustained delivery of the Aβ interferer or p75 receptor interferer to a subject for less than 30 days after administration of the Aβ interferer or p75 receptor interferer to the subject. For example, the pharmaceutically acceptable formulation, eg, "slow release" formulation, may offer sustained delivery of the Aβ interferer or p75 receptor interferer to a subject for one, two, three or four weeks after the administration of a interferente of .Aß or integer of receptor p75 to the subject. Alternatively, the pharmaceutically acceptable formulation can offer sustained delivery of the Aβ interferer or p75 receptor interferer to a subject for more than 30 days after administration to the subject of the Aβ interferent or interferer of the p75 receptor. The pharmaceutical formulation employed in the method of the present invention contains a therapeutically effective amount of the Aβ interferer or p75 receptor interferer. A "therapeutically effective amount" refers to an effective amount, in dosages and for periods of time necessary to achieve the desired result. A therapeutically effective amount of the Aβ interferent or p75 receptor interferer may vary according to factors such as disease status, age, and subject weight, and the ability of the Aβ interferer or p75 receptor interferer (alone or in combination with one). or various other agents) of eliciting a desired response in a subject. Dosage regimens can be adjusted to provide the optimal therapeutic response. A therapeutically effective amount is also an amount in which any toxic or negative effect of the Aβ-interfering or p75-interfering receptor is overcompensated by the therapeutically beneficial effects. A non-limiting range for the therapeutically effective concentration of the Aβ interferent or the p75 receptor interferent is 100 μM to 1 mM. It is also understood that for a particular subject, specific dosage regimens must be adjusted over time according to the individual's need and judgment professional of the person administering or supervising the administration of the Aβ interferer or p75 receptor interferer and that the dosage ranges presented herein are for purposes of example only and are not intended to limit the scope or practice of the claimed invention. In vitro treatment of neuronal cells Neurons, such as for example central nervous system neurons, or isolated neuronal cells can additionally come in contact with a therapeutically effective amount of an Aβ interferer or p75 receptor interferer, in vitro. Accordingly, neuronal cells can be isolated from a subject and can be cultured in vitro, using well-known techniques. In summary, a culture of neuronal cells can be obtained by allowing neuron cells to migrate out of fragments of neuronal tissue that adhere to a suitable substrate (e.g., a culture dish) or by tissue disintegration, e.g. mechanically or enzymatically, to produce a suspension of neuronal cells. For example, the enzymes trypsin, collagenase, elastase, hyaluronidase, DNase, pronase, dispase, or various combinations thereof may be employed. Trypsin and pronase provide the most complete disintegration but can damage cells. The collagenase and the dispase provide a less complete disintegration but are less harmful Methods for isolating tissue (e.g., neuronal tissue) and tissue disintegration to obtain cells (e.g., neuronal cells) are described in Freshney R.I., Culture of Animal Cells, A Manual of Basic Technique. 3rd edition, 1994, whose contents are incorporated here by reference. Such cells can subsequently be contacted with an Aβ interfering or p75 receptor interfering at levels and for a time in accordance with that described above. Once the inhibition of neuronal cell death is achieved, these neuronal cells can be readministered to the subject, for example, by implantation. States characterized by neuronal cell death induced by Aβ and / or mediated by p75 receptor. The present invention also relates to a method for the treatment of a disease characterized by neuronal cell death induced by Aβ and / or mediated by p75 receptor on a subject. As used herein, the term "disease" is recognized in the art, and includes a disorder, disease or condition characterized by neuronal cell death induced by Aβ and / or mediated by p75 receptor. Examples of disorders of this type include Alzheimer's disease, dementias related to Alzheimer's disease (such as, for example, Pick), Parkinson's disease and other diffuse Lewy body diseases, multiple sclerosis, amyotrophic lateral sclerosis, progressive supranuclear palsy, and spongiform encephalitis. The invention further illustrates through the following examples, that they should not be considered as limiting. The contents of all references, patents and published patent applications cited in this application are incorporated herein by reference. EXAMPLES Differentiated PC-12 cells of NGF were treated with fibrillar Aβ or Aβ42 fibrillar in the presence or absence of Aβ interfering. The percentage of dead cells was determined by MTT and SRB assays (protein counting with 15 rhodamine-based stain) (in accordance with that described, for example, in Rubinstein L.V. et al. (1990) J. Nati. Cancer Inst. 82 (13): 1113-8) after 24 hours of incubation. The cells were incubated with Aβ40 with the same ratio 1: 1 or 1: 2 weight: weight. The contents of all references, patents issued as well as published patent applications cited in this application including the background, are incorporated herein by reference. Equivalents 25 Experts in the field will recognize or may determine by the use of only routine experiment numerous equivalents to the specific procedures described here. Such equivalents are considered within the • scope of the present invention and the following claims encompass said equivalents. 10 fifteen twenty 25 Appendix A AMINOPHOSPHONATES Code Name Structure NC-796 3- [2- (1, 2, 3, 4-tetrahydro-isoquinolinyl)] -1-propanphospho- single, disodium salt NC-831 3-aminopropylphosphonic acid Hj H; CH CH; P? H: NC-849 (S) -2-amino-2-methyl-4- acid phosphonobutanoic NC-850 D (-) -2-amino-4-phosphono- butanoic NC-851 L- (+) -2-amino-4-phosphonic acid butanoic OR II NC-860 3-aminopropyl) methyl) phos- H2N ^ - ^ P-OH • HCl Me Fínico, hydrochloride CH2CH2CH2P03H2 NC-876 (R) - (-) - 3- (2-carboxy-H-perazin-4-yl) -propyl-1-phosphoro-OO-H (D-CPP) H acid CHJCH-CHPOJH: NC-890 (R, E) -4- (3-phosphonoprop-2-enyl) piperazine-2-carboxylic acid C H rPCOyONa); NC-1520 cis-L-4-phosphonomethylproline, trisodium salt disodium salt NC-1565 1- (3-phosphonopropyl) -benzimide-15-zol, disodium salt NC-1568 3-dimethylamino-l-propyl acid phosphonic, disodium salt 20 NC-1667 3-amino-butylphosphonic acid, disodium salt , P? 3Na2 NC-1668 3-amino-pentylphosphonic acid, NH2 disodium salt 25 NC-1669 3-amino-hexyl phosphonic acid, disodium salt NC-1670 3-amino-heptyl phosphonic acid, POjNa: disodium salt NC-1671 3-amino-octylphos phonic acid, PC-.Na- disodium salt NC-1672 3-amino-4-methyl-pentyl-phosphonic acid, disodium salt POjNa; NC-1673 3-amino-3-methyl-butyl-NH, phosphonic acid, disodium salt NC-1674 3-amino-3-phenylpropylphosphonic acid, disodium salt NC-1675 3-amino-4-phenyl-butyl-phosphonic acid, disodium salt NC- 1676 3-amino-4-phenyl-pentylphosphonic acid, disodium salt NC- 1677 3-amino-3-phenyl-butyl-phosphonic acid, disodium salt NC-1678 2-amino-2- (2-phosphonoethyl) -1,3,4-trihydronaphthalene, disodium salt NC-1679 1-amino-1- (2-phosphonoethyl) -cydohexane, disodium salt NC-1680 2- ( 2-amino-4-phosphonobutoxy) tetrahydropyran NC-1681 3-amino-4-hydroxybutylphosphonic acid, disodium salt NC-1704 2-pyrrolidinylphosphonate Diethyl NC-1705 2-pyrrolidinylphospho- single, disodium salt NC-1706 1, l-dioxo-2- (3-phosphonopropyl) -isothiazoline, salt di sodium HO NC-1708 2-deoxy-2-phosphonoacetyl- < / OH V? H amino-D-glucose H? NHCOCH2 fiP (ONa) 2 NC-1713 3-hydroxy-3- (2-pyridyl) propenyl-2-phosphonic acid, disodium salt 5 NC-1714 3-hydroxy-3- (3-pyridyl) propeni-1-2-phonic acid, disodium salt NC-1715 3-hydroxy-3- (4-pyri-flp 10 diD propenyl-2-phosphonic acid, disodium salt NC-1716 3-amino-3- (2-pyridyl) propenyl-2-phosphonic acid, disodium salt NC-1717 3-amino-3- (3-pyridyl) propenyl-2-phosphonic acid, disodium salt disodic 25 NC-1719 1, 4-diamino-l- (3-pi- ridyl) buti1-2-phosphonic, disodium salt NC-1720 1,4-diamino-4-methyl-5- 1- (3-pyridyl) pentyl) -2-phosphonic acid, disodium salt NC-1721 1, 4-diamino-4-methyl-1- (2-pyridyl) pentyl-2-tk-10-phosphonic acid, disodium salt NC-1722 1,4-diamino-4-methyl-1- (4-pyridyl) pentyl-2-phosphonic acid, disodium salt 15 NC-1728 3- (2-amino-4, 5, 7, 8-tetrahydro-6H-thiazolo [4, 5-d] azepin-6-yl) propylphosphonic, disodium salt 20 NC-1769 N-phosphonomethylglycine: OVPCH, NHCH; COCH NC-1770 N-phosphonomethylglycine, salt (NaO); PCH, NriCH: trisodium COONa 25 NC-1773 acid (2R, 4S) -4-phosphonome- Tilpipecolinic, trisodium salt NC-1774 (2R, 4S) -4-phosphonomethyl-pi- O pecolinamide, disodium salt .P (ONa) j? N I CIINH2 H O NC-1781 N-phosphonomethylglycine O (Aldrich, see NC-1769) ?? HO) 2CH, NHCH: COOH ( NC-1782 N-phosphonomethylglycine, trisodium salt 0 II (see NC1770, pre (NaO> 2PCH2NHCH: COONa stopped from NC1781) NC-1784 3- [6-methoxy-2- (1, 2, 3, 4-tetrahydroisoquinolinyl)] M? P propylphosphonic acid, disodium salt NC-1785 3- [8-methoxy-2 acid - (1, 2, 3, 4-tetrahydroisoquinolinyl)] propyl phosphonic, disodium salt NC-1786 3- [2- (3-methoxycarbo- nil-1, 2, 3, 4-tetrahydroiso-quinolinyl)] -propylphospho- single, disodium salt NC-1787 2- (3-phosphonopropyl) -l, 2,3,4-tetrahydro-9H-pyrido [3, 4-b] indole, disodium salt 110 15 20 25 BISPHOSPHONATES Code Name Structure NC-1702 pamidronic acid (3-aminopropyl-1-hydroxypropan-1, 1-bisphosphonic acid) P? 3 a2 NC-1703 3-amino-l-hydroxyprop-OH pan-1, 1-bisphosphonic acid, tetrasodium salt NC-1710 l-amino-3-sulfopropan-PO, H, 1, 1-bisphosphonic acid I NH, PC Na, NC-1711 l-amino-3-sulfopropan-a03S ^^ v ^ P? 3Ña2 1 1, 1-bisphosphonic acid, penta- NK- salt, sodium NC-1723 1,3-diaminopropan-1, 1- POjNa acid, bisphosphonic acid, tetrasó- H, N salt. PC ^ Ña, NH, dica POjNa, NC-1724 l-amino-3-dimethylamino-N POjÑa, propan-1, 1-bis-phosphonic acid, NH-salt, tetrasodium NC-1725 3-dimethylamino-l-hydroxypropan-1, 1-bisphosphonic acid, tetrasodium salt • 5 NC-1726 l-hydroxy-3- (methylphenyl-PCsNa- - OjÑ, amino) -propan-1, 1-bisphosphonic acid OH tetrasodium salt NC-1727 l-amino-3- (methylphenyl-) acid (10 min) propan-1, 1-bisphosphonic, tetrasodium salt NC-1732 ibandronic acid, tetrasodium salt (l-hydroxy-3- (methylpentylamino) -propan-1, 1- acid bisphosphonic, tetrasodium salt) • NC-1733 l-amino-3- (methylpentyl-P? 3 a2 ^ PO, Na. Amino) propan-1, 1-bisphosphonic acid, NH, tetrasodium salt NC-1734 l-amino-3- (1-benzimidazole) propan-l, 1-bisphosphonic acid 25 NC-1735 l-amino-3- (1-benzimide- zolyl) propan-l, 1-bisphosphonic, tetrasodium salt NC-1736 3-aminopropan-1, 1-bis-H, N .POjNa, phosphonic acid, tetrasodium salt POjNa2 NC-1737 (di) -3-aminobutan-1, 1-. PCA Na; NH: POj a, bisphosphonic, tetrasodium salt NC-1738 acid (diJ-3-aminopentan-l, 1-bisphosphonic, tetrasodium salt NC-1739 (di) -S-'aminohexan-l, 1- .PO, Na: bisphosphonic acid, tetrasóNH POjNa salt: dica NC-1740 (di) -3-aminoheptan-l, 1-bisphosphonic acid, salt tetrasó dica NC-1741 (di) -3-aminooctan-l, 1- acid bisphosphonic, tetrasodium salt AC NC-1743 (di) -3-amino-3-methyl-NH2 P? 3Na acid, butan-1, 1-bisphosphonic acid, tetrasodium salt AlO NC-1744 (di) -3-amino-3-phenyl-propan-1, 1-bisphosphonic acid, salt tetrasodic NC-1745 (di) -3-amino-4-phenyl-15-butan-1, 1-bisphosphonic acid, salt tetrasodic NC-1746 (di) -3-amino-4-phenyl-pentan-1, 1-bisphosphonic acid, tetrasodium salt NC-1747 (di) -3-amino-3-phenyl-butan-1, 1-bisphosphonic acid, salt tetrasodica 25 NC-1748 (di) -2- (2-amino-1, 2, 3, 4-tetrahydronaphthalenyl) acid 1, 1-bisphosphonic, tetrasodium salt NC-1749 2- (1-aminociclohexyl) ethan-1, 1-bisphosphonic acid, salt tetrasodic tetrasodic NC-1751 (di) -3-amino-4-hydroxy-POPONa acid, ÑH2 POjNa; butan-1, 1-bisphosphonic, tetrasodium salt 15 NC-1752 (S) -hydroxy (2-pyrroli- NAP VN »AP dinyl) methan-bisphosphonic acid, tetrasodium salt 20 HO or NC-1753 hydroxy acid [2S, 4R) -4-hydro- NAPH H xi -2 - pir rol idinil] me tanbis phosphonic, tetrasodium salt OH 25 NC-1754 2-amino-l-hydroxyethane-OH HjCHiQPOjNa acid,): 1, 1-bisphosphonic, tetrasodium salt NC-1755 1,2-diaminoethane-1, NH, acid • CH, C (P? 3.Na ^ Bisphosphonic, tetrasodium salt NC-1756 4-amino-l-hydroxybutan- 1, 1-bisphosphonic, tetrasodium salt NC-1757 1-, 4-diaminobutan-l, 1- NH2 N?, CH, CH, CH, C (P03Na2) 2 bisphosphonic acid, tetrasodium salt NC-1758 5-amino-l-hydroxypentan- 1, 1-bisphosphonic, tetrasodium salt NC-1759 1, 5-diaminopentan-l, 1- acid bisphosphonic, tetrasodium salt NC-1760 (S) -2-amino-l-hydroxypropan-1, 1-bisphosphonic acid, salt tetrasodic NC-1761 (S) -2-amino-l-hydroxy-NH2 butan-1, 1-bis-phosphonic acid, tetrasodium OH salt NH2 NC-1762 (S) -2-amino-l-hydroxy-Y-POjN j I? U 3-methylbutan-l, 1-bisphosphono- OH acid co, tetrasodium salt • 5 NC-1763 (S) -2-amino-l-hydroxy-3-phenylpropan-l, 1-bisphosphonic acid, tetrasodium salt NC-1764 (S) -2-amino-l, 3-dihydroxypropan-1,1-bisphosphonic acid co, tetrasodium salt NC-1765 (S) -2, 3-diamino-l-hydroxypropan-1, 1-bisphosphoni- NK acid, 15 co, tetrasodium salt -POjNa; OH NC-1766 (di) -3-amino-l-hydroxy-3-phenylpropan-l, 1-bis- acid phosphonic, tetrasodium salt 20 to NC-1767 (S) -3-amino-2- (4-chlorophenyl) -1-hydroxypropan-1, 1-bisphosphonic acid, tetraHjN salt. rPOjNa2 OH sodium 25 NC-1768 (S) -2-amino-3- (4-aminophenyl) -1-hydroxypropan-l acid, 1-bisphosphonic, tetrasodium salt Phosphonocarboxylate Derivatives Code Name Structure NC-769 phosphonoacetic acid (phosphonet) 5 NC-770 phosphonoformic acid, triO II salt NaO ^ ^ P- ONa sodium ONa NC-829 2-carboxyethylphosphonic acid H02CCH, CH, P03H: NH2 NC-832 (di) -2-amino-3-phosphono acid - HOjOaiCHjPQiHj 15 propanoic NC-834 (di) -2-amino-5-phosphono- NH2 HOzCCHCHzCHjC POjH-j pentanoic acid • NC-837 phosphonoacetic acid (see NC-HO, CCH2P? 3H2 20 769) NC-849 (S) -2-amino-2-methyl-4-phosphonobutanoic acid NC-850 D- (-) -2-amino-4-phospho- 25 -butanoic acid NC-851 L- (+) -2-amino-4-phospho-COzH H, N -butanoic H "pa; oH > NC-852 • D- (-) -2-amino-7-phospho- O (0H) acid, 5 noheptanoico NC-853 L- (+) -2-amino-7-phospho-CO, H H, N ... noheptanoic acid .PO (OH), nohexanoic NC-855 L- (+) -2-amino-6-phosphohexaenoic acid 15 NC-856 D- (-) -2-amino-4-phospho- nopentanoic NC-857 L- (+) -2-amino-4-phospho-CO, H H, N .. PCXOH), 20 nopentanoic NC-858 D - (-) - 2-amino-3-phospho- nopropanoic NC-859 L- (+) -2-amino-3-phospho- 25 nopropanoic NC-876 (R) - (-) -3- (2-carboxy-piperazin-4-yl) -propyl-1-CH, CH, CH, P03H, phosphonic acid (D-CPP) -N.

CCsH H NC-879 L-4- [difluoro (phosphono) methyl)] -phenylalanine NC-890 acid (R, E) -4- (3-phosphonoprop- NC-1519 trans-L-4-phosphonomethylproline, trisodium salt NC-1520 cis-L-4-phosphonomethylproline, trisodium salt NC-1571 N, N-diethyl phosphonoacetamide, disodium salt C-158 N-cyclohexy-1-phosphonoacetamide, disodium salt NC-1587 phosphonoacetic hydrazide, disodium salt a 5 NC-1588 N-hydroxyphosphonoacetamide, disodium salt ? C-1591 N- phosphonoacetyl-L-alanine,? - 0 trisodium salt ? C-1593 N-phosphonoacetyl-glycine, trisodium salt fifteen ? C-1595 N- (phosphono-active) -L-aspara- • gin-L-glycine, tetrasodium salt 20 HO) 2PCH2? HCH2COOH? C-1769 N-phosphonomethylglycine OR C-1770 N-phosphonomethylglycine, salt II (? AO) 2PCH2? HCH2COO? A trisodium 25 NC-1771 2-phosphonomethylglutaric acid co, tetrasodium salt NC-1772 2-phosphonomethylsuccinic acid, tetrasodium salt O -P (ONa); NC-1773 (2R, 4S) -4-phosphonomethyl-pipecolinic acid, trisodium salt O-PCONa); NC-1774 (2R, 4S) -4-phosphonomethyl-pipe-cholineamide, disodium salt OR I I NC-1781 N-phosphonomethylglycine HO), PCH, NHCH; CO0H (Aldrich, see NC-1769) NC-1782 N-phosphonomethylglycine, OII (NaO) salt, PCH, trisodium NHCH2COONa (see NC1770, prepared from NC 1781) NC-1786 3- [2- (3-methoxycarbo- nil-1, 2, 3, 4-tetrahydroiso- quinolinyl)] -propylphosphonic, disodium salt PHOSPHONATE DERIVATIVES Code Name Structure NC-796 3- [2- (1,2,3,4-tetrahydroisoquinolinyl)] -l-propan- phosphonic, disodium salt NC-825 propylphosphonic acid NC-826 ethylphosphonic acid CH3CH, P? 3H, CH3PO3H, NC-827 methylphosphonic acid NC-828 tert-butylphosphonic acid (H3) 3CP? 3H2 NC-830 phenylphosphonic acid NC-831 3-aminopropylphosphonic acid NH2CH, CH CH PO '3n H2 NC-833 (1-aminopropyl) phosphono- NH2 CH3CH2CH-P03H2 nico NC-836 diethyl phosphoramidate O H2N-P-PCH7CHi) 2 NC-860 3-ami- O H, 'P-OH • HCl nopropyl) methyl) phosphinic acid hydrochloride Me NC-1563 4-amino-l-butylphospho- O.PÍO a nico acid, disodium salt H, N 0 NC-1565 1- (3-phosphonopropyl) -benziII CH2CH, Cri; P (ONa), midazole, disodium salt -Ñ11- > NC-1568 3-dimethylamino-l-pro- 0 II Mc, NCH2CH2CH, P (ONa), Pilphosphonic acid, disodium salt NC-1573 diphenylamine-4-phosphonic acid, disodium salt .P03Na2 NC-1667 3-amino-butylphosphono-NH, single, disodium salt NC-1668 3-amino-pentylphosphonic acid, disodium salt POiNa, NC-1669 3-amino-hexylphospho- single, disodium salt NC-1670 3-amino-heptylphosphonic acid, disodium salt NC-1671 3-amino-octyl phosphonic acid, disodium salt NC-1672 3-amino-4-methyl-pentylphosphonic acid, disodium salt NC-1673 3-amino-3-methyl-bu- \ .P ^ Na, tylphosphonic acid, disodium salt NH, NC-1674 3-amino-3-phenylpropylphosphonic acid, disodium salt NC-1675 3-amino-4-phenylbutylphosphonic acid, disodium salt NC-1676 3-amino-4-phenyl-pentylphosphonic acid, disodium salt NC-1677 3-amino-3-phenyl-butylphosphonic acid disodium salt NC-1678 2-amino-2- (2-phosphonoethyl) - 1, 3, 4-trihydronaphthalene, disodium salt NC-1679 1-amino-1- (2-phosphonoethyl) -cydohexane, disodium salt NC-1680 2- (2-amino-4-phosphonobutoxy; tetrahydropyran ^ P NC-1681 3-amino-4-hydroxy-bu- HO '-POjNa acid; 5-tolphosphonic, disodium salt NH, NC-1701 3-phosphonopropansulfonic acid flfcOfcPv ^^ ^ - SOj a nico, trisodium salt sole, disodium salt 15 NC-1706 1, l-dioxo-2- (3-phosphonopropyl) -isothiazoline, disodium salt NC-1708 2-deoxy-2-phosphonoacetyl-20 amino-D-glucose NC-1713 3-hydroxy-3- (2-pyridyl) propenyl-2-phosphonic acid, disodium salt 25 NC-1714 3-hydroxy-3- (3-pyridyl) propenyl-2-phosphonic acid, disodium salt 5 NC-1715 3-hydroxy-3- (4-pyridyl) propenyl-2-phosphonic acid, disodium salt NC-1716 3-amino-3- (2-pyridyl) -propenyl-2-phosphonic acid, disodium salt NC-1717 3-amino-3- (3-pyridyl) propenyl-2-phosphonic acid, disodium salt NC-1718 3-amino-3- (4-pyridyl) propenyl-2-phosphonic acid, disodium salt 0 NC-1719 l, 4-diamino-1- (3-pyridyl) butyl-2-phosphonic acid , disodium salt 5 NC-1720 acid 1, -diamino-4-methyl- 1- (3-pyridyl) pentyl-2-phosphonic, disodium salt NC-1721 1,4-diamino-4-methyl-1- (2-pyridyl) pentyl-2-phosphonic acid, disodium slade NC-1722 1,4-diamino-4-methyl-1- (4-pyridyl) pentyl-2-phosphonic acid, disodium salt NC-1728 3- (2-amino-4, 5, 7, 8-tetrahydro-6H-thiazolo [4,5-] d] azepin-6-yl) propyl-phosphonic, disodium salt NC-1784 3- [6-methoxy-2- (1, 2, 3, 4-tetrahydroisoquinolinyl)] propyl phosphonic, disodium salt NC-1785 3- [8-methoxy-2- (1, 2, 3, 4-tetrahydroisoquinolinyl)] propylphosphonic acid, salt dica NC-1787 2- (3-phosphonopropyl) -1, 2, 3, 4-tetrahydro-9H-pyrido [3, 4- b] indole, disodium salt • 15 20 25 PHOSPHONOCARBOHYDRATES Code Structure name • NC-1708 2-deoxy-2-phosphonoacetylanu.no-D-glucose NC-1709 2-deoxy-2-thiophosphonoacetylamino-D-glucose NC-1793 ß, D-glucopyranosylmethylphosphonic acid, disodium salt 15 NC-1794 a-D-glucopyranosylmethylphosphonic acid, disodium salt • 20 NC-1795 6-deoxy-6-C-phosphonomethyl-D-glucono-d-lactone, disodium salt p NC-1796 6-deoxy-6-C-phosphonomethyl-1-D-CH, P (ONa), glucose, disodium salt 1 H & X HO OH NC-1798 3-deoxy-3-C-phosphonomethyl-D-glucose, disodium salt 0 NC-1799 1-deoxy-N-phosphonoacetyl rimicina, disodium salt NC-1801 (1, 5-dideoxy-1, 5-amino-15 a-D-glucopyranosyl) methylphosphonic acid, disodium salt 25 THIOPHOSPHONATE DERIVATIVES Code Name Structure NC-1521 thiophosphonoforic acid, salt 5 Trisodium NC-1522 thiophosphonacetic acid = 1-0 NC-1523 thiophospho-acetic acid, salt trisodium 15 NC-1524 thiophospho-acetic acid, triethyl ester 20 NC-1525 chlorine (thiophosphon) acetic acid, trisodium salt NC-1526 dichloro (thiophosphonic acid) acid 25 tico, trisodium salt NC-1527 thiophosphonomethylthiophosphate acid S 11 II phonic, tetrasodium salt NaO ^ "^ - ^ .P \ \ - ONa NaO ONa NC-1528 phenylthiophosphinomethylthio- phosphonic, trisodium salt NC-1529 3- [2- (1, 2, 3, 4-tetrahydro- isoquinolinyl)] -1-propantiofosphonic, disodium salt NC-1530 propylthiophosphonic acid CH3CH, CH, P02H, 15 S NC-1531 ethyl alcoholic acid CH3CH, P02H2 20 NC- 1532 phonic methylophonic acid S NC-1533 tert-butyl thiophosphonic acid (Cfy ^ CPC ^ H- 25 NC-1534 2-carboxyethylthiophosphonic acid NC-1536 phenylthiophosphonic acid O-1 P? 2H2 NC-1537 3-aminopropylthiophosphonic acid > m CH ^ CH ^ OH ^ r0 NC-1538 (di) -2-amino-3-thiophosphonic acid- propionic NC-1539 acid (1-aminopropyl) thiophosphonium-NHj S CH3CH, CH-P (OH.

NC-1540 (di) -2-amino-5-thiophosphonic acid- pentanoic 0 NC-1541 (S) -2-amino-2-methyl-4-thio-phosphonobutanoic acid NC-1542 D-2-amino-4-thiophosphonobuta- acid 5 noico NC-1543 L-2-amino-4-thiophosphonobuta- noico • .0 NC-1545 L-2-amino-7-thiophosphono-hepta-acid noico NC-1546 D-2-amino-6-thiophosphonohexane acid 15 noico NC-1547 L-2-amino-6-thiophosphonohexane acid noico 20 NC-1548 D-2-amino-4-thiophosphopentane acid noico 25 NC-1549 L-2-amino-4-thiophosphopentanoic acid NC-1550 D-2-amino-3-thiophosphonopro- piomco NC-1551 L-2-amino-3-thiophosphonopro- COjH S? ^ - 0 pionic acid H ' H, N '• p-OH-HCl NC-1552 3-aminopropyl (methyl) thiophosic acid-Mephine, hydrochloride 15 NC-1553 (R) -3- (2-carboxypiperazine- CH, CH, CH, P (OH), I fl 4-yl) -propyl-1-thiophosphonic acid 'CO, H H 20 NC-1554 L-4- [(difluoro (thiophosphono) methyl)] -phenylalanine 25 NC-1555 (R, E) -4- (3-thiophosphonoprop-2-enyl) piperazine-2-carboxylic acid NC-1556 trans-L-4-thiophosphonomethylproline, trisodium salt NC-1557 cis-L-4-thiophosphonomethylproline, trisodium salt NC-1564 4-amino-1-butylthiophospho-S ^ PIONAIN, disodium salt H2N " NC-1566 1- (3-thiophosphonopropyl) -benzimi¬ -CH, CH2CH: P (ONa) j dazol, disodium salt • N NC-1569 3-dimethylamino-l-propyl-thiophosphonic acid, disodium salt Me, NCH, CTl2CH2PCONa > .

NC-1572 N, N-diethylthiophosphonoacetamide, disodium salt NC-1574 diphenylamine-4-thiophosphonic acid, disodium salt NC-1575 selenophosphoformic acid, trisodium salt NC-1576 selenophosphonic acid, salt trisodium NC-1577 D-2-amino-3-selenophosphono- propanoic NC-1578 L-2-amino-3-selenophosphono- propanoic NC-1579 D-2-amino-4-selenophosphono- butanoic H, *.? " HE NC-1580 L-2-amino-4-selenophos phono-U ^ ^ ^^ D? I,? H PÍOr butanoico NC-1585 N-cyclohexy1thiophosphonoacetamide, disodium salt •? C-1586 N-cyclohexylselenophosphonoacetamide, disodium salt ? C-1589 N-hydroxythiophosphonoacetamide, salt disodic ? C-1590 thiophosphonoacetic hydrazide, salt disodic trisodium salt ? C-1594 N-thiophosphonoacetyl-L-glycine, 20 trisodium salt ? C-1596 N- (thiophospho-acetyl) -L-asparagin-L-glycine, tetrasodium salt 25? C-1599 (S) -2-pyrrolidinmethylthio- acid phosphonic, disodium salt NC-1707 1, l-dioxo-2- (3-thiophosphonopro- • phenyl) -isothiazolidine, salt dica NC-1709 2-deoxy-2-thiophosphonoacetyla- H ° or mino-D-glucose NHCOCH ^ ONa); hydro-6H-thiazolo [4, 5-d] azepin-6-yl) propylthiophosphonic, disodium salt 15 twenty 25

Claims (1)

1. CLAIMS A method for inhibiting neuronal cell death induced by Aβ, comprising contacting a neuronal cell with an interfering Aβ in such a way that neuronal cell death is inhibited. The method according to claim 1, wherein said Aβ interferer interferes with the ability of the Aβ peptide to form amyloid fibrils. The method according to claim 1, wherein said Aβ interferer interferes with the ability of Aβ peptide to bind to a cell surface molecule. The method according to claim 3, wherein said cell surface molecule is a neutrophic receptor. The method according to claim 4, wherein said neutrophic receptor is the p75 receptor related to apoptosis. The method according to claim 3, wherein said cell surface molecule is a glycosaminoglycan. The method according to claim 3, wherein said Aβ peptide is in soluble form. The method according to claim 3, wherein said .Aβ peptide is in the form of fibril. 9. The method according to claim 1, wherein the Aß interferer has the following structure: 10. The method according to claim 1, wherein said Aβ interferer is selected from the group consisting of ethanesulfonic acid, 1,2-ethanedisulfonic acid, 1-propanesulfonic acid, 1,3-propanedisulfonic acid, 1,4-butanedisulfonic acid. , 1,5-pentanedisulfonic acid, 2-aminoethanesulfonic acid, 4-hydroxybutan-1-sulfonic acid and pharmaceutically acceptable salts thereof. The method according to claim 1, wherein said Aβ interferer is selected from the group consisting of 1-butanesulfonic acid, 1-decansulfonic acid, 2-propanesulfonic acid, 3-pentanesulfonic acid, 4-heptanesulfonic acid, and pharmaceutically acceptable salts thereof. The method according to claim 1, wherein said Aβ interferer is 1,7-dihydroxy-4-heptanesulfonic acid or a pharmaceutically acceptable salt thereof. 13. The method according to claim 1, wherein said .Aß interferer is 3-amino-1-propanesulfonic acid or a salt thereof. 14. The method according to claim 1, wherein said interferer of Aß has the following structure: X • - (CY1Y2) nC (X) XR3 RXX wherein Z is XR2 or R4; R1 and R2 are each, independently, hydrogen, a ? Substituted or unsubstituted aliphatic group, an aryl group, a heterocyclic group, or a salt formation cation; R3 is hydrogen, lower alkyl, aryl, or a salt formation cation; R4 is hydrogen, lower alkyl, aryl or amino; X independently for each case, is O or S; Y "and Y2 are, independently, each hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, or aryloxy, and 20 n is an integer from 0 to 12. 15. A method for providing neuroprotection to a subject, which it comprises the administration of an Aβ interfering agent to said subject, in such a way that said neuroprotection is provided. The method according to claim 15, wherein said Aβ interferer interferes with the ability of the Aβ peptide to bind to a cell surface molecule. 17. The method according to claim 16, wherein said cell surface molecule is a neurotrophic receptor. 18. The method according to claim 17, wherein said neurotrophic receptor is the p75 receptor related to apoptosis. 19. The method according to claim 16, wherein said cell surface molecule is a glycosaminoglycan. 20. The method according to claim 16, wherein said Aβ peptide is in soluble form. 21. The method according to claim 16, wherein said Aβ peptide is in the form of fibril. 22 The method according to claim 15, wherein the interferer of Aβ has the following structure: Q [Y "X +] n 23. The method according to claim 15, wherein said Aβ interferer is selected from the group consisting of Ethanesulfonic acid, 1,2-ethanedisulfonic acid, 1-propanesulfonic acid, 1,3- propandisulfonic acid, 1,4-butanedisulfonic acid, 1,5-pentanedisulfonic acid, 2-aminoethanesulfonic acid, 4-hydroxybutan-1-sulfonic acid and pharmaceutically acceptable salts thereof. 24. The method according to claim 15, wherein said Aβ interferer is selected from the group consisting of 1-butanesulfonic acid, 1-decansulfonic acid, 2-propanesulfonic acid, 3-pentanesulfonic acid, 4-heptanesulfonic acid, and pharmaceutically acceptable salts thereof. 25. The method according to claim 15, wherein said A > is 1, 7-dihydroxy-4-heptanesulfonic acid or a pharmaceutically acceptable salt thereof. 26. The method according to claim 15, wherein said Aβ interferer is 3-amino-1-propanesulfonic acid or a salt thereof. 27. The method according to claim 15, wherein said interferer of Aß has the following structure: X - (CY1Y2) nC (X) XR3 RX 25 where Z is XR2 or R4; R1 and R2 are each, independently, hydrogen, a substituted or unsubstituted aliphatic group, an aryl group, a heterocyclic group, or a salt formation cation; R3 is hydrogen, lower alkyl, aryl, or a salt-forming cation; R 4 is hydrogen, lower alkyl, aryl or amino; X independently for each case, is 0 or S; Y1 and Y2 are each independently hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, or aryloxy; and n is an integer from 0 to 12. 28. The method according to claim 15, wherein said Aβ-interferer is administered in a pharmaceutically acceptable formulation. 29. The method according to claim 28, wherein said pharmaceutically acceptable formulation is a dispersion system. 30. The method according to claim 29, wherein said pharmaceutically acceptable formulation comprises a lipid-based formulation. 31. The method according to claim 30, wherein said pharmaceutically acceptable formulation comprises a liposome formulation. 32. The method according to claim 31, wherein said pharmaceutically acceptable formulation comprises a multivesicular liposome formulation. 33. The method according to claim 29, wherein said pharmaceutically acceptable formulation comprises a polymer matrix. 34. The method according to claim 33, wherein said polymer matrix is selected from the group consisting of naturally derived polymers such as for example albumin, alginate, cellulose derivatives, collagen, fibrin, gelatin and polysaccharides. 35. The method according to claim 33, wherein said polymer matrix is selected from the group consisting of synthetic polymers such as polyesters (PLA, PLGA), polyethylene glycol, poloxomers, polyanhydrides, and pluronics. 36. The method according to claim 33, wherein said polymer matrix is in the form of microspheres. 37. The method according to claim 28, wherein the pharmaceutically acceptable formulation provides sustained delivery of said Aβ interfering to a subject. 38. A method for the treatment of a disease characterized by the death of neuronal cells induced by Aβ in a subject, said method comprises the administration of an Aβ interferer to said subject, in such a way that said disease characterized by neuronal cell death induced by Aβ is treated. 39. A method for inhibiting neuronal cell death mediated by the p75 receptor, comprising contacting a neuronal cell with a p75 receptor interferer having the structure: Q [Y "X +] n where Y" is a anionic group at physiological pH; Q is a vehicle group; X + is a cationic group; and n is an integer selected such that the biodistribution of the p75 receptor interferer for a predicted target site is not impeded while maintaining the activity of the p75 receptor interferer, provided that the p75 receptor interferer is not chondroitin sulfate A , in such a way that the death of neuronal cells is inhibited. 40. A method for providing neuroprotection to a subject, comprising administering to said subject a p75 receptor interferer having the structure: Q [Y "X +] n where Y" is an anionic group at physiological pH; Q is a vehicle group; X + is a cationic group; and n is an integer selected such that the biodistribution of the p75 receptor interferer is prevented for a predicted target site while maintaining the activity of the p75 receptor interferer, provided that the p75 receptor interferer is not chondroitin sulfate A , in such a way that neuroprotection is provided. 41. A method for the treatment of a disease in a subject characterized by neuronal cell death mediated by the p75 receptor, comprising administering to said subject a p75 receptor interferer having the structure: Q [Y ~ X +] n where Y "is an anionic group at physiological pH, Q is a vehicle group, X + is a cationic group, and n is an integer selected in such a way that the biodistribution of the p75 receptor interferer is not prevented for a targeted target site while the activity of the p75 receptor interferer is maintained, provided that the p75 receptor interferer is not chondroitin A sulfate, such that the disease characterized by neuronal cell death mediated by the p75 receptor is treated. to inhibit the death of neuronal cells mediated by the receptor p75, comprising the contacting of a neuronal cell with a p75 receptor interferer having the structure: X - (CY1Y2) nC (X) XR3 RX wherein Z is XR2 or R4; R1 and R2 are each independently hydrogen, a substituted or unsubstituted aliphatic group, an aryl group, a heterocyclic group, or a salt formation cation; R3 is hydrogen, lower alkyl, aryl or a salt formation cation; R 4 is hydrogen, lower alkyl, aryl or amino; X is, independently for each case, O or S; Y1 and Y2 are each, independently hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, or aryloxy; and n is an integer from 0 to 12 such that the death of neuronal cells is inhibited. , A method for providing neuroprotection to a subject, comprising administering said subject of a p75 receiver interferer that has the structure: X - (CYxY2) nC (X) XR3 RX wherein Z is XR2 or R4; R1 and R2 are each independently hydrogen, a substituted or unsubstituted aliphatic group, an aryl group, a heterocyclic group, or a salt formation cation; R3 is hydrogen, lower alkyl, aryl, or a salt formation cation; R 4 is hydrogen, lower alkyl, aryl or amino; X is, independently for each case, O or S; Y1 and Y2 are each independently hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, or aryloxy; and n is an integer from 0 to 12 such that neuroprotection is provided. . A method for the treatment of a disease in a subject, said disease is characterized by the death of neuronal cells mediated by the p75 receptor, said The method comprises administering to said subject a p75 receptor interferer having the structure: X RX wherein Z is XR2 or R4; R1 and R2 are each independently hydrogen, a substituted or unsubstituted aliphatic group, an aryl group, a heterocyclic group, or a salt formation cation; R3 is hydrogen, lower alkyl, aryl or a salt formation cation; R 4 is hydrogen, lower alkyl, aryl or amino; X is, independently for each case, O or S; Y1 and Y2 are independently hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, or aryloxy; and n is an integer from 0 to 12 such that said disease characterized by neuronal cell death mediated by the p75 receptor is treated.